Dithio etp derivatives

ABSTRACT

Disclosed herein, inter alia, are compositions and methods of using the same for the treatment of cancer.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication No. 62/395,244 filed on Sep. 15, 2016 and U.S. ProvisionalApplication No. 62/433,678 filed on Dec. 13, 2016, which areincorporated herein by reference in their entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant no.1F32CA180741 awarded by the National Cancer Institute. The governmenthas certain rights in the invention.

BACKGROUND

ETP natural products represent an intriguing class of (typically) fungalsecondary metabolites with a large variety of biological activitiesranging from antibiotic to antiviral to antimalarial properties. Highlevels of toxicity, however, have so far prevented any clinical studiesof known ETP structures. Furthermore, modification of properties such aswater solubility, membrane permeability or metabolic stability inbiological systems is critical. Accordingly, a synthetic route tosynthesize ETP analogues for medicinal purposes is imperative and hassignificant value. Disclosed herein, inter alia, are solutions to theseand other problems in the art.

BRIEF SUMMARY OF THE INVENTION

In an aspect is provided a compound having the formula:

or a pharmaceutically acceptable salt thereof. R¹ is hydrogen, halogen,—N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(1A), —NR^(1B)R^(1C),—C(O)OR^(1A), —C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D), —S(O)_(n1)R^(1B),—SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R² ishydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —COOR^(2A),—CONR^(2B)R^(2C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R³ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(3A),—R^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸. R⁵ is —C(O)-L²-R¹⁹ or—C(S)-L²-R¹⁹. R⁴ and R⁵ may optionally be joined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene. L² is a bond, —O—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene. R¹⁸ and R¹⁹ are independently halogen, substituted orunsubstituted C₁-C₃alkyl, substituted or unsubstituted aryl. R²⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(25A),—NR^(25B)R^(25C), —C(O)OR^(25A), —C(O)NR^(25B)R^(25C), —NO₂, —SR^(25D),—S(O)_(n25)R^(25B), —SO_(v25)NR^(25B)R^(25C), —NHNR^(25B)R^(25C),ONR^(25B)R^(25C), —NHC(O)NHNR^(25B)R^(25C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C),R^(3A), R^(3B), R^(3C), R^(3D), R^(25A), R^(25B), R^(25C), and R^(25D)are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH2,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCCl₃,—OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R^(1B) and R^(1C), R^(2B) andR^(2C), R^(3B) and R^(3C), and R^(25B) and R^(25C) substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. The symbol z3 is an integer from 0 to 5. The symbols n1, n3,and n25 are independently an integer from 0 to 4. The symbols v1, v3,and v25 are independently 1 or 2.

In an aspect is provided a pharmaceutical composition including acompound as described herein and a pharmaceutically acceptableexcipient.

In an aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient, a compound as described herein,and at least one anticancer agent.

In an aspect is provided a method of treating cancer, includingadministering to a subject in need thereof a therapeutically effectiveamount of a compound as described herein, including embodiments.

In another aspect is provided a method of inhibiting the growth of acancer cell, comprising administering to a subject in need thereof atherapeutically effective amount of a compound or composition describedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Chemical scaffolds I-IV. Each R is independently a group thatcould be removed in vivo, such as for example —C(O)R, —C(S)R′,—C(O)NR′₂, —SR′, —S(O₂)R′, —S(O) R′, or —S(O)NR₂.

FIGS. 2A and 2B. In vitro cytotoxicity against two invasive cancer celllines, DU145 (human prostate cancer) and A2058 (human melanoma) weredetermined for different analogs.

FIG. 3. Depicts the effect ofS,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)diethanethioate on in vivo inhibition of cutaneous T-cell lymphoma(CTCL) in mice.

DETAILED DESCRIPTION

Provided herein, inter alia, are synthetic analogues of ETP compounds.The analogues may be used in the treatment of cancer and may beeffective when synergistically combined with other cancer treatingcompounds. Methods of synthesis and use are also provided.

I. DEFINITIONS

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals. The alkyl may include a designated number ofcarbons (e.g., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclizedchain. Examples of saturated hydrocarbon radicals include, but are notlimited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—). Analkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynylmoiety. An alkyl moiety may be fully saturated. An alkenyl may includemore than one double bond and/or one or more triple bonds in addition tothe one or more double bonds. An alkynyl may include more than onetriple bond and/or one or more double bonds in addition to the one ormore triple bonds.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) maybe placed at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Heteroalkyl is an uncyclized chain. Examples include, but arenot limited to:

—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g.,O, N, S, Si, or P). A heteroalkyl moiety may include two optionallydifferent heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include three optionally different heteroatoms (e.g., O, N, S, Si,or P). A heteroalkyl moiety may include four optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefive optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include up to eight optionally differentheteroatoms (e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,

1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. A 6,5-fused ring heteroarylene refers to two ringsfused together, wherein one ring has 6 members and the other ring has 5members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl,

1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl,2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituentsfor each of the above noted aryl and heteroaryl ring systems areselected from the group of acceptable substituents described below. An“arylene” and a “heteroarylene,” alone or as part of anothersubstituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. A heteroaryl group substituent may be —O—bonded to a ring heteroatom nitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.,all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “thio,” as used herein, means a sulfur that is single bonded tocarbon or to another sulfur.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃,

—CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substitutedor unsubstituted C₁-C₅ alkyl or substituted or unsubstituted 2 to 5membered heteroalkyl). In embodiments, the alkylarylene isunsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”, “cycloalkyl,”“heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′,

—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN,—NO₂, —NRSO₂R″, —NR′C═(O)R″, —NR′C(O)—OR″, —NR′OR″, in a number rangingfrom zero to (2m′+1), where m′ is the total number of carbon atoms insuch radical. R, R′, R″, R′″, and R″″ each preferably independentlyrefer to hydrogen, substituted or unsubstituted heteroalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl (e.g., arylsubstituted with 1-3 halogens), substituted or unsubstituted heteroaryl,substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, orarylalkyl groups. When a compound of the invention includes more thanone R group, for example, each of the R groups is independently selectedas are each R′, R″, R′″, and R″″ group when more than one of thesegroups is present. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-,or 7-membered ring. For example, —NR′R″ includes, but is not limited to,1-pyrrolidinyl and 4-morpholinyl. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen,

—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂,fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C═(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″, R′″, andR″″ are preferably independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. When a compound of the invention includes morethan one R group, for example, each of the R groups is independentlyselected as are each R′, R″, R′″, and R″″ groups when more than one ofthese groups is present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one or morefloating substituents (including, but not limited to, points ofattachment to the remainder of the molecule), the floating substituentsmay be bonded to the heteroatoms. Where the ring heteroatoms are shownbound to one or more hydrogens (e.g. a ring nitrogen with two bonds toring atoms and a third bond to a hydrogen) in the structure or formulawith the floating substituent, when the heteroatom is bonded to thefloating substituent, the substituent will be understood to replace thehydrogen, while obeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—,

—CRR′—, or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X′—(C″R″R′″)_(d)—, where s and d are independently integersof from 0 to 3, and X′ is —O—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. Thesubstituents R, R′, R″, and R′″ are preferably independently selectedfrom hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron(B), Arsenic (As), and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

(A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, NHNH₂, ONH2, NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃,—OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C₈ cycloalkyl,C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl), and

-   -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo,        -   halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH,            —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        -   —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,        -   —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,            —OCI₃,—OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, unsubstituted alkyl            (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),            unsubstituted heteroalkyl (e.g., 2 to 8 membered            heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered            heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈            cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),            unsubstituted heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), unsubstituted aryl (e.g.,            C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted            heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9            membered heteroaryl, or 5 to 6 membered heteroaryl), and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo,            -   halogen, —CCl₃, —CBr₃, —CF₃, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH,            -   —O₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,                —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂,                —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl,                C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl                (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered                heteroalkyl, or 2 to 4 membered heteroalkyl),                unsubstituted cycloalkyl (e.g., C3-C₈ cycloalkyl, C3-C6                cycloalkyl, or C5-C6 cycloalkyl), unsubstituted                heterocycloalkyl (e.g., 3 to 8 membered                heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5                to 6 membered heterocycloalkyl), unsubstituted aryl                (e.g., C6-C₁₀ aryl, C₁₀ aryl, or phenyl), or                unsubstituted heteroaryl (e.g., 5 to 10 membered                heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6                membered heteroaryl), and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo,            -   halogen, —CCl₃, —CBr₃, —CF₃, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₃H,            -   —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,            -   —NHC(O)NH₂, —NHSO₂H,            -   —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,                —OCI₃,—OCHCl₂, —OCHBr₂,            -   —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl,                C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl                (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered                heteroalkyl, or 2 to 4 membered heteroalkyl),                unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆                cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted                heterocycloalkyl (e.g., 3 to 8 membered                heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5                to 6 membered heterocycloalkyl), unsubstituted aryl                (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or                unsubstituted heteroaryl (e.g., 5 to 10 membered                heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6                membered heteroaryl).

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl isa substituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds, generally recognized as stable bythose skilled in the art, are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“S_(p)”, “S_(t)”, or “S_(n)” refers to a sulfide bridge having p, t, orn sulfurs (e.g. S₂ is —S—S—, S₃ is —S—S—S—, S₄ is —S—S—S—S—).

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

Descriptions of compounds of the present invention is limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereininclude those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

The terms “treating”, or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, include prevention of an injury,pathology, condition, or disease. In embodiments, treating does notinclude preventing.

A “therapeutically effective amount” or “effective amount” is an amountsufficient for a compound to accomplish a stated purpose relative to theabsence of the compound (e.g. achieve the effect for which it isadministered, treat a disease, reduce enzyme activity, increase enzymeactivity, reduce a signaling pathway, or reduce one or more symptoms ofa disease or condition). An example of an “effective amount” is anamount sufficient to contribute to the treatment, prevention, orreduction of a symptom or symptoms of a disease, which could also bereferred to as a “therapeutically effective amount.” A “reduction” of asymptom or symptoms (and grammatical equivalents of this phrase) meansdecreasing of the severity or frequency of the symptom(s), orelimination of the symptom(s). The exact amounts will depend on thepurpose of the treatment, and will be ascertainable by one skilled inthe art using known techniques (see, e.g., Lieberman, PharmaceuticalDosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technologyof Pharmaceutical Compounding (1999); Pickar, Dosage Calculations(1999); and Remington: The Science and Practice of Pharmacy, 20thEdition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In some embodiments inhibition refers toreduction of a disease or symptoms of disease. In some embodiments,inhibition refers to a reduction in the activity of a particular proteinor nucleic acid target. Thus, inhibition includes, at least in part,partially or totally blocking stimulation, decreasing, preventing, ordelaying activation, or inactivating, desensitizing, or down-regulatingsignal transduction or enzymatic activity or the amount of a protein.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

“Patient,” “subject,” “patient in need thereof,” and “subject in needthereof” are herein used interchangeably and refer to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with the compounds ormethods provided herein.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethylcellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intranasal or subcutaneous administration, or the implantation of aslow-release device, e.g., a mini-osmotic pump, to a subject.Administration is by any route, including parenteral and transmucosal(e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal). Parenteral administration includes, e.g., intravenous,intramuscular, intra-arteriole, intradermal, subcutaneous,intraperitoneal, intraventricular, and intracranial. Other modes ofdelivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

By “co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies, for exampleepigenetic inhibitors or multi-kinase inhibitors. The compound of theinvention can be administered alone or can be co-administered to thepatient. Co-administration is meant to include simultaneous orsequential administration of the compound individually or in combination(more than one compound or agent). Thus, the preparations can also becombined, when desired, with other active substances (e.g. to reducemetabolic degradation).

The compositions disclosed herein can be delivered by transdermally, bya topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. Oral preparations include tablets, pills,powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups,slurries, suspensions, etc., suitable for ingestion by the patient.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositionsdisclosed herein can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions can also be delivered asnanoparticles.

Pharmaceutical compositions may include compositions wherein the activeingredient (e.g. compounds described herein, including embodiments orexamples) is contained in a therapeutically effective amount, i.e., inan amount effective to achieve its intended purpose. The actual amounteffective for a particular application will depend, inter alfa, on thecondition being treated. When administered in methods to treat adisease, such compositions will contain an amount of active ingredienteffective to achieve the desired result, e.g., modulating the activityof a target molecule, and/or reducing, eliminating, or slowing theprogression of disease symptoms.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated, kind of concurrent treatment, complications from thedisease being treated or other health-related problems. Othertherapeutic regimens or agents can be used in conjunction with themethods and compounds of Applicants' invention. Adjustment andmanipulation of established dosages (e.g., frequency and duration) arewell within the ability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease means thatthe disease is caused by (in whole or in part), a symptom of the diseaseis caused by (in whole or inpart) the substance or substance activity orfunction, or a side-effect of the compound (e.g. toxicity) is caused by(in whole or inpart) the substance or substance activity or function.

As used herein, the term “cancer” refers to all types of cancer,neoplasm, or malignant tumors found in mammals, including leukemia,carcinomas and sarcomas. Exemplary cancers include acute myeloidleukemia (“AML”), chronic myelogenous leukemia (“CML”), and cancer ofthe brain, breast, pancreas, colon, liver, kidney, lung, non-small celllung, melanoma, ovary, sarcoma, and prostate. Additional examplesinclude, cervix cancers, stomach cancers, head & neck cancers, uteruscancers, mesothelioma, metastatic bone cancer, Medulloblastoma,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis,primary macroglobulinemia, primary brain tumors, cancer, malignantpancreatic insulanoma, malignant carcinoid, urinary bladder cancer,premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer,neuroblastoma, esophageal cancer, genitourinary tract cancer, malignanthypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms ofthe endocrine and exocrine pancreas, and prostate cancer

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). The murine leukemia model is widely accepted as beingpredictive of in vivo anti-leukemic activity. It is believed that acompound that tests positive in the P388 cell assay will generallyexhibit some level of anti-leukemic activity regardless of the type ofleukemia being treated. Accordingly, the present invention includes amethod of treating leukemia, including treating acute myeloid leukemia,chronic lymphocytic leukemia, acute granulocytic leukemia, chronicgranulocytic leukemia, acute promyelocytic leukemia, adult T-cellleukemia, aleukemic leukemia, a leukocythemic leukemia, basophylicleukemia, blast cell leukemia, bovine leukemia, chronic myelocyticleukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia,Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, and undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas which can be treated with a combination ofantineoplastic thiol-binding mitochondrial oxidant and an anticanceragent include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas which can betreated with a combination of antineoplastic thiol-binding mitochondrialoxidant and an anticancer agent include, for example, acral-lentiginousmelanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman'smelanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma,lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungalmelanoma, and superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas which can be treated with acombination of antineoplastic thiol-binding mitochondrial oxidant and ananticancer agent include, for example, acinar carcinoma, acinouscarcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinomaadenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolarcell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloidcarcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma,bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma,cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma,comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma encuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cellcarcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma,encephaloid carcinoma, epiermoid carcinoma, carcinoma epithelialeadenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum,gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma,carcinoma gigantocellulare, glandular carcinoma, granulosa cellcarcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellularcarcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroidcarcinoma, infantile embryonal carcinoma, carcinoma in situ,intraepidermal carcinoma, intraepithelial carcinoma, Krompecher'scarcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticularcarcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelialcarcinoma, carcinoma medullare, medullary carcinoma, melanoticcarcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum,carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum,mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oatcell carcinoma, carcinoma ossificans, osteoid carcinoma, papillarycarcinoma, periportal carcinoma, preinvasive carcinoma, prickle cellcarcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reservecell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma,scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma,carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidalcell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamouscarcinoma, squamous cell carcinoma, string carcinoma, carcinomatelangiectaticum, carcinoma telangiectodes, transitional cell carcinoma,carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, andcarcinoma villosum.

Cancer model organism, as used herein, is an organism exhibiting aphenotype indicative of cancer, or the activity of cancer causingelements, within the organism. The term cancer is defined above. A widevariety of organisms may serve as cancer model organisms, and includefor example, cancer cells and mammalian organisms such as rodents (e.g.mouse or rat) and primates (such as humans). Cancer cell lines arewidely understood by those skilled in the art as cells exhibitingphenotypes or genotypes similar to in vivo cancers. Cancer cell lines asused herein include cell lines from animals (e.g. mice) and from humans.

An “anticancer agent” as used herein refers to a molecule (e.g.compound, peptide, protein, nucleic acid, antibody) used to treat cancerthrough destruction or inhibition of cancer cells or tissues. Anticanceragents may be selective for certain cancers or certain tissues. Inembodiments, anticancer agents herein may include epigenetic inhibitorsand multi-kinase inhibitors.

An “epigenetic inhibitor” as used herein, refers to an inhibitor of anepigenetic process, such as DNA methylation (a DNA methylationInhibitor) or modification of histones (a Histone ModificationInhibitor). An epigenetic inhibitor may be a histone-deacetylase (HDAC)inhibitor, a DNA methyltransferase (DNMT) inhibitor, a histonemethyltransferase (HMT) inhibitor, a histone demethylase (HDM)inhibitor, or a histone acetyltransferase (HAT). Examples of HDACinhibitors include Vorinostat, romidepsin, CI-994, Belinostat,Panobinostat, Givinostat, Entinostat, Mocetinostat, SRT501, CUDC-101,JNJ-26481585, or PCI24781. Examples of DNMT inhibitors includeazacitidine and decitabine. Examples of HMT inhibitors include EPZ-5676.Examples of HDM inhibitors include pargyline and tranylcypromine.Examples of HAT inhibitors include CCT077791 and garcinol.

A “multi-kinase inhibitor” is a small molecule inhibitor of at least oneprotein kinase, including tyrosine protein kinases and serine/threoninekinases. A multi-kinase inhibitor may include a single kinase inhibitor.Multi-kinase inhibitors may block phosphorylation. Multi-kinasesinhibitors may act as covalent modifiers of protein kinases.Multi-kinase inhibitors may bind to the kinase active site or to asecondary or tertiary site inhibiting protein kinase activity. Amulti-kinase inhibitor may be an anti-cancer multi-kinase inhibitor.Exemplary anti-cancer multi-kinase inhibitors include dasatinib,sunitinib, erlotinib, bevacizumab, vatalanib, vemurafenib, vandetanib,cabozantinib, poatinib, axitinib, ruxolitinib, regorafenib, crizotinib,bosutinib, cetuximab, gefitinib, imatinib, lapatinib, lenvatinib,mubritinib, nilotinib, panitumumab, pazopanib, trastuzumab, orsorafenib.

“Selective” or “selectivity” or the like of a compound refers to thecompound's ability to discriminate between molecular targets (e.g. acompound having selectivity toward HMT SUV39H1 and/or HMT G9a).

“Specific”, “specifically”, “specificity”, or the like of a compoundrefers to the compound's ability to cause a particular action, such asinhibition, to a particular molecular target with minimal or no actionto other proteins in the cell (e.g. a compound having specificitytowards HMT SUV39H1 and/or HMT G9a displays inhibition of the activityof those HMTs whereas the same compound displays little-to-no inhibitionof other HMTs such as DOT1, EZH1, EZH2, GLP, MLL1, MLL2, MLL3, MLL4,NSD2, SET1b, SET7/9, SET8, SETMAR, SMYD2, SUV39H2).

“HMT SUV39H1,” “SUV39H1,” or “suppressor of varigation 3-9 homolgue 1”is a histone methyltransferase protein that trimethylates H3K9 (NCBI GINo. 49456451). HMT SUV39H1 may methylate H3K9.

“HMT G9a” or “G9a” is a histone methyltransferse that dimethylates H3K9(NCBI GI No. 287865). HMT G9a may dimethylate H3K9.

“H3K9 trimetylation” refers to tri-methylation of lysine 9 of HistoneH3. H3K9 trimethylation may be performed by histone methyl transferasessuch as SUV39H1.

Azacitidine is an epigenetic inhibitor having the formula:

including pharmaceutically acceptable salts thereof.

Azacitidine is an anti-cancer epigenetic inhibitor.

Decitabine is an epigenetic inhibitor having the formula:

including pharmaceutically acceptable salts thereof.

Decitabine is an anti-cancer epigenetic inhibitor.

Sorafenib is a multi-kinase inhibitor having the formula:

including pharmaceutically acceptable salts thereof.

Sorafenib is an anti-cancer multi-kinase inhibitor.

The terms “synergy”, “synergism” “synergistic” and “synergistictherapeutic effect” are used herein interchangeably and refer to ameasured effect of compounds administered in combination where themeasured effect is greater than the sum of the individual effects ofeach of the compounds administered alone as a single agent.

II. COMPOUNDS

In an aspect is provided a compound having the formula:

or a pharmaceutically acceptable salt thereof.

R¹ is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(1A),—NR^(1B)R^(1C), —C(O)OR^(1A), —C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D),—S(O)_(n1)R^(1B), SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R² is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —COOR^(2A),—CONR^(2B)R^(2C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R² is C₁-C₃alkyl. In embodiments, R² is methyl.

R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R³ is C₁-C₃alkyl. In embodiments, R³ is methyl.

R⁴ is —C(O)—O-L¹-R¹⁸ or —C(S)-L¹-R¹⁸. R⁵ is —C(O)-L²-R¹⁹ or—C(S)-L²-R¹⁹. R⁴ and R⁵ may optionally be joined to form:

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene. L² is a bond, —O—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene. R⁴ and R⁵ may optionally be joined to form:

R¹⁸ and R¹⁹ are independently halogen, OH, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl.

In embodiments, R¹⁸ and R¹⁹ are independently halogen. In embodiments Vand R¹⁹ are independently —Cl. In embodiments R¹⁸ and R¹⁹ areindependently —OH. In embodiments, R¹⁸ and R¹⁹ are independentlysubstituted or unsubstituted C₁-C₃alkyl or substituted or unsubstitutedaryl. In embodiments, R¹⁸ and R¹⁹ are independently unsubstitutedC₁-C₃alkyl or unsubstituted aryl.

R²⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(25A), —NR^(25B)R^(25C), —C(O)OR^(25A), —C(O)NR^(25B)R^(25C), —NO₂,—SR^(25D), —S(O)_(n25)R^(25B), —SO_(v25)R^(25B)R^(25C),—NHNR^(25B)R^(25C), ONR^(25B)R^(25C), —NHC(O)NHNR^(25B)R^(25C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(3A), R^(3B),R^(3C), R^(3D), R^(25A), R^(25B), R^(25C), and R^(25D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C),and R^(25B) and R^(25C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

The symbol z3 is an integer from 0 to 5. The symbols n1, n3, and n25 areindependently an integer from 0 to 4. The symbols v1, v3, and v25 areindependently 1 or 2.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R²⁵ is hydrogen.

In embodiments, the compound has the formula:

(Ia), wherein R¹, z3, R², R³, R⁴, and R⁵ are as described herein.

Ring A is a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, Ring A issubstituted or unsubstituted phenyl, substituted or unsubstitutedpyridyl, substituted or unsubstituted pyrazolyl, substituted orunsubstituted imidazolyl, substituted or unsubstituted oxazolyl,substituted or unsubstituted isoxazolyl, substituted or unsubstitutedthiazolyl, substituted or unsubstituted furanyl, substituted orunsubstituted pyrrolyl, or substituted or unsubstituted thienyl. Inembodiments, Ring A is substituted or unsubstituted phenyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

In embodiments, the compound has the formula:

wherein R¹, z3, R², R³, R⁴, and R⁵ are as described herein.

X¹ is N or CR¹⁰. X² is N or CR¹¹. X³ is N or CR¹². R⁶ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(6A),—NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂, —SR^(6D),—SO_(n6)R^(6B), —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C),—ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, X¹ is CR¹⁰ and X³ is CR¹². In embodiments,X¹ is CR¹⁰; X² is N; X³ is CR¹²; R⁶, R⁷ and R¹⁰ are independentlyhydrogen; and R¹² is —OCH₃.

R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂, —SR^(6D),—SO_(n6)R^(6B), —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C),—ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D),—SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), —CONR^(10B)R^(10C), —NO₂,—SR^(10D), —SO_(n10)R^(10B), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(11A), —NR^(11B)R^(11C), —COOR^(11A), —CONR^(11B)R^(11C), —NO₂,—SR^(11D), —SO_(n11)R^(11B), —SO_(v11)NR^(11B)R^(11C),—NHNR^(11B)R^(11C), —ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁰ and R¹¹ may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl.

R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(12A), —NR^(12B)R^(12C), —COOR^(12A), —CONR^(12B)R^(12C), —NO₂,—SR^(12D), —SO_(n12)R^(12B), —SO_(v12)NR^(12B)R^(12C),—NHNR^(12B)R^(12C), —ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ and R¹² may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen. In embodiments, R¹¹ is hydrogen. Inembodiments, R¹² is hydrogen.

R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(10A),R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C), R^(11D), R^(12A),R^(12B), R^(12C), and R^(12D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(6B) and R^(6C), R^(7B) and R^(7C), R^(10B) andR^(10C), R^(11B) and R^(11C), and R^(12B) and R^(12C), substituentsbonded to the same nitrogen atom may independently optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl.

The symbols n6, n7, n10, n11 and n12 are independently an integer from 0to 4. Each occurrence of v6, v7, v10, v11, v12, is independently 1 or 2.

In embodiments, R¹⁰ and R¹¹ or R¹¹ and R¹² are optionally joined to forma substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl having structural formula:

In embodiments, R¹⁰ and R¹¹ are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹¹ and R¹² are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹⁰ and R¹¹ or R¹¹ and R¹² are optionally joined to forma substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl having structural formula:

In embodiments, R¹⁰ and R¹¹ are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹¹ and R¹² are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

X⁶ is O, NR^(23A), or S. X⁷ is O, NR^(24A), or S. The symbol z4 is aninteger from 0 to 2. The symbol z5 is an integer from 0 to 8. The symbolm is 1 or 2. R²¹ and R²² are independently halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, the symbol z4 is 0. In embodiments, the symbol z4 is 0.

R^(23A), and R^(24A) are independently hydrogen, halogen, —N₃, —CF₃,—CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, the compound has the formula:

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

wherein R⁵, R⁶, R¹⁰, R¹¹, X¹, X², and X³ are as described herein.R^(1.1), R^(1.2), R^(1.3), and R^(1.4) are encompassed by the definitionof R¹ or are independently hydrogen. R²⁴ is —C(O)-L¹-R¹⁸ or—C(S)-L¹-R¹⁸. R²⁵ is —C(O)-L²-R¹⁹ or —S(S)-L²-R¹⁹. R²⁴ and R²⁵ mayoptionally be joined to form:

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene. L² is a bond, —O—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene. R¹⁸ and R¹⁹ are as described herein.

In embodiments, the compound has the formula:

wherein R², R³, R⁴, and R⁵ are as described herein. R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are substituents encompassed by thedefinitions of R¹ or hydrogen.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁴ is hydrogen. In embodiments, R⁵ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen.

R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO,—OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A), —CONR^(1.2B)R^(1.2C),—NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B), —SO_(v1.2)NR^(1.2B)R^(1.2C),—NHNR^(1.2B)R^(1.2C), —ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R^(1.2) is hydrogen, —CN, —CHO, —OR^(1.2A),—NR^(1.2B)R^(1.2C), —C(O)OR^(1.2A), —C(O)NR^(1.2B)R^(1.2C), —NO₂,—SR^(1.2D), —S(O)_(n1.2)R^(1.2B), —SO_(v1.2)NR^(1.2B)R^(1.2C),—NHNR^(1.2B)R^(1.2C), ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.2) is hydrogen,—CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂, —C(O)OCH₃, —S(O)₂R^(1.2B), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.2) is—C(O)OR^(1.2A) wherein R^(1.2A) is substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(1.2) is an unsubstituted C₁-C₃ alkyl. In embodiments, R^(1.2) is —CN.In embodiments, R^(1.2) is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃,—C(O)OCH₃, —C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₃, or

In embodiments, R^(1.2) is methyl substituted with substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, and R^(1.3) is CN. These embodiments apply to all formulaein the application.

In embodiments, R^(1.2) is methyl substituted with morpholinyl, andR^(1.3) is CN. In embodiments, R^(1.2) is methyl substituted with BOCsubstituted piperazinyl, and R^(1.3) is CN.

R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A), —CON^(1.3B)R^(1.3C), —NO₂,—SR^(1.3D), —SO_(n1.3)R^(1.3B), —SO_(v1.3)NR^(1.3B)R^(1.3C),—NHNR^(1.3B)R^(1.3C), —ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R^(1.3) is —CN.In embodiments, R^(1.3) is —CN and R^(1.2) is an unsubstituted C₁-C₃alkyl. In embodiments, R^(1.3) is —CN and R^(1.2) is methyl.

In embodiments, R^(1.3) is hydrogen, —CN, —CHO, —OR^(1.3A),—NR^(1.3B)R^(1.3C), —C(O)OR^(1.3A), —C(O)NR^(1.3B)R^(1.3C), NO₂,—SR^(1.3D), —S(O)_(n1.3)R^(1.3B), —SO_(v1.3)NR^(1.3B)R^(1.3C),—NHNR^(1.3B)R^(1.3C), ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.3) is hydrogen,—CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂, —C(O)OCH₃, —S(O)₂R^(1.3B), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.3) is—C(O)OR^(1.3A) wherein R^(13A) is substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(1.3) is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃,

—C(O)OC(CH₃)₃, or

R^(1.4) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.4A), —NR^(1.4B)R^(1.4C), —COOR^(1.4A), —CONR^(1.4B)R^(1.4C),—NO₂, —SR^(1.4D), —SO_(n1.4)R^(1.4B), —SO_(v1.4)NR^(1.4B)R^(1.4C),—NHNR^(1.4B)R^(1.4C), —ONR^(1.4B)R^(1.4C), —NHC(O)NHNR^(1.4B)R^(1.4C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R^(1.5) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.5A), —NR^(1.5B)R^(1.5C), —COOR^(1.5A), —CONR^(1.5B)R^(1.5C),—NO₂, —SR^(1.5D), —SO_(n1.5)R^(1.5B), —SO_(v1.5)NR^(1.5B)R^(1.5C),—NHNR^(1.5B)R^(1.5C), —ONR^(1.5B)R^(1.5C), —NHC(O)NHNR^(1.5B)R^(1.5C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A), and R^(1.2B), R^(1.2C),R^(1.2D), R^(1.3A), R^(1.3B), and R^(1.3C), R^(1.3D), R^(1.4A),R^(1.4B), R^(1.4C), and R^(1.5D), R^(1.5A), R^(1.5B), R^(1.5C), andR^(1.5D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R^(1.1B) and R^(1.1C), R^(1.2B) and R^(1.2C), andR^(1.3B) and R^(1.3C) substituents bonded to the same nitrogen atom mayindependently optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. The symbols n1.2, n1.3, n1.4, and n1.5 are independently aninteger from 0 to 4. The symbols, v1.2, v1.3, v1.4, and v1.5 areindependently 1 or 2.

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene. L² is a bond, —O—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedhetero alkylene.

In embodiments, L¹ is —O—. In embodiments, L¹ is —NH—. In embodiments,L¹ is a bond. In embodiments, L² is —O—. In embodiments, L² is —NH—. Inembodiments, L² is a bond.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5), R², R³, R⁴, R⁵, R⁶,R⁷, R¹⁰, R¹², and X² are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen. In embodiments, R¹² is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.2), R^(1.3), R², R³, R⁶, R⁷, R¹⁰, R¹², R¹⁸, R¹⁹, and X² areas described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen. In embodiments, R¹² is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5), R², R³, R⁴, R⁵, R⁶,R⁷, R¹⁰, R¹², and X² are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen. In embodiments, R¹² is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.1), R^(1.2), R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, X⁶, X⁷, R²¹, andz4 are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen. In embodiments, R²¹ is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5), R², R³, R⁴, R⁵, R⁶,and R⁷ are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁴ is hydrogen. In embodiments, R⁵ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.2), R^(1.3), R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, X⁶, X⁷, R²¹, andz4 are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁴ is hydrogen. In embodiments, R⁵ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.2), R^(1.3), R², R³, R⁴, R⁵, R⁶, R⁷, R¹², X⁶, X⁷, R²¹, andz4 are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹² is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.2), R^(1.3), R², R³, R⁴, R⁵, R⁶, R⁷, R¹², R²¹, and z4 areas described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹² is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.2), R^(1.3), R², R³, R⁴, R⁵, R⁶, R⁷, R¹², X⁶, X⁷, R²¹, andz4 are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹² is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.2), R^(1.3), R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, X⁶, X⁷, R²¹, andz4 are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.2), R^(1.3), R^(1.4), R^(1.5), R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰,X⁶, X⁷, R²¹, and z4 are as described herein.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R¹⁰ is hydrogen.

In embodiments, the compound has the formula:

wherein R^(1.1), R^(1.2), R^(1.3), R², R³, R⁴, and R⁵ are as describedherein. X⁴ is N or CR¹³. X⁵ is CR¹⁴R¹⁵, S, O, or NR^(20A).

R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(8A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C), —NO₂, —SR^(8D),—SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂, —SR^(9D),—SO_(n9)R^(9B), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(13A), —NR^(13B)R^(13C), —COOR^(13A), —CONR^(13B)R^(13C), NO₂,—SR^(13D), —SO_(n13)R^(13B), —SO_(v13)NR^(13B)R^(13C),—NHNR^(13B)R^(13C), —ONR^(13B)R^(13C), —NHC(O)NHNR^(13B)R^(13C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R¹⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(14A), —NR^(14B)R^(14C), —COOR^(14A), —CONR^(14B)R^(14C), —NO₂,—SR^(14D), —SO_(n14)R^(14B), —SO_(v14)NR^(14B)R^(14C),—NHNR^(14B)R^(14C), —ONR^(14B)R^(14C), —NHC(O)NHNR^(14B)R^(14C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R¹⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(15A), —NR^(15B)R^(15C), —COOR^(15A), —CONR^(15B)R^(15C), —NO₂,—SR^(15D), —SO_(n15)R^(15B), —SO_(v15)NR^(15B)R^(15C),—NHNR^(15B)R^(15C), —ONR^(15B)R^(15C), —NHC(O)NHNR^(15B)R^(15C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R^(20A) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(15A), —NR^(15B)R^(15C), —COOR^(15A), —CONR^(15B)R^(15C), —NO₂,—SR^(15D), —SO_(n15)R^(15B), —SO_(v15)NR^(15B)R^(15C),—NHNR^(15B)R^(15C), —ONR^(15B)R^(15C), —NHC(O)NHNR^(15B)R^(15C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁸ is hydrogen. In embodiments, R⁹ is hydrogen. Inembodiments, R¹³ is hydrogen. In embodiments, R¹⁴ is hydrogen. Inembodiments, R¹⁵ is hydrogen. In embodiments, R^(20A) is hydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

wherein R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5), R², R³, R⁴, R⁵, X⁴,X⁵, R⁸, R⁹, R^(B), R¹⁴, and R¹⁵ are as described herein.

R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(13A),R^(13B), R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D), R^(15A),R^(15B), R^(15C), R^(15D), and R^(20A) are independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(13B) and R^(13C), R^(14B) and R^(14C), and R^(15B) and R^(15C),substituents bonded to the same nitrogen atom may independentlyoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

In embodiments, R^(13B) and R^(13C), R^(14B) and R^(14C), and R^(15B)and R^(15C) substituents bonded to the same nitrogen atom mayindependently optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl.

The symbols n8, n9, n13, n14, and n15 are independently an integer from0 to 4. The symbols v8, v9, v13, v14, and v15 are independently 1 or 2.

R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(13A),R^(13B), R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D), R^(15A),R^(15B), R^(15C), and R^(15D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁸ is hydrogen. In embodiments, R⁹ is hydrogen. Inembodiments, R¹³ is hydrogen. In embodiments, R¹⁴ is hydrogen. Inembodiments, R¹⁵ is hydrogen.

In embodiments, the compound isS,S′-3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)diethanethioate.

In embodiments, the compound is a compound described herein in Example2.

In embodiments, R¹ is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1A), —NR^(1B)R^(1C), —C(O)OR^(1A), —C(O)NR^(1B)R^(1C), —NO₂,—SR^(1D), —S(O)_(n1)R^(1B), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), x substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹ is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹ is substitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R¹ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R¹ is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R¹ is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R¹ is unsubstituted C₁-C₆ alkyl. In embodiments, R¹ isunsubstituted C₁-C₄ alkyl. In embodiments, R¹ is —CN or —CH₃. Inembodiments, R¹ is —CN. In embodiments, R¹ is —CH₃.

In embodiments, R¹ is hydrogen, —CN, —CHO, —OR^(1A), —NR^(1B)R^(1C),—C(O)OR^(1A), —C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D), —S(O)_(n1)R^(1B),—SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), or substituted or unsubstituted alkyl. Inembodiments, R¹ is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(1B), or substituted or unsubstituted alkyl. Inembodiments, R¹ is —C(O)OR^(1A) wherein R^(1A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R¹ is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R¹ is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹ is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹ isR²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹ is R²⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹ is R²⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹ is R²⁶-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹ is R²⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, le is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹ is R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹ is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹ is R²⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹ is R²⁶-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R¹ is R²⁶-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R¹ is R²⁶-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1A) is R^(26A)_substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1B) is R^(26B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1C) is R^(26C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1D) is R^(26D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R² is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—COOR^(2A), —CONR^(2B)R^(2C), substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R² is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R² is substitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R² is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R² is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R² is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R² is unsubstituted C₁-C₆ alkyl. In embodiments, R² isunsubstituted C₁-C₄ alkyl. In embodiments, R² is —CH₃.

In embodiments, R² is R²⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁷-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁷-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁷-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R² is R²⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R² isR²⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R² is R²⁷-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R² is R²⁷-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R² is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R² is R²⁷-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R² is R²⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R² is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R² is R²⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R² is R²⁷-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R² is R²⁷-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R² is R²⁷-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R² is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R² is R²⁷-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R² is R²⁷-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R² is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(2A) is R^(27A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(27A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(27A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(27A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(27A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(27A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(2B) is R^(27B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(27B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(27B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(27B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(27B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(27B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(2C) is R^(27C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(27C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(27C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(27C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(27C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(27C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂,—SR^(3D), —SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R³ is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³ is substitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R³ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R³ is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R³ is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R³ is unsubstituted C₁-C₆ alkyl. In embodiments, R³ isunsubstituted C₁-C₄ alkyl. In embodiments, R³ is —CH₃.

In embodiments, R³ is an unsubstituted cyclopropyl. In embodiments, R³is an unsubstituted cyclobutyl. In embodiments, R³ is an unsubstitutedcyclopentyl. In embodiments, R³ is an unsubstituted cyclohexyl. Inembodiments, R³ is an unsubstituted C₂-C₄ alkyene. In embodiments, R³ isan unsubstituted C₄ alkyene.

In embodiments, R³ is R²⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁸-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁸-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁸-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R³ is R²⁸-substituted or unsubstituted C₁-C₄ alkyl,wherein R²⁸ is substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³ is R²⁸-substituted or unsubstituted C₁-C₄ alkyl,wherein R²⁸ is substituted or unsubstituted heterocycloalkyl (e.g., 3 to8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R²⁸ is morpholino.

In embodiments, R³ is R²⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³ isR²⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³ is R²⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³ is R²⁸-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³ is R²⁸-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³ is R²⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³ is R²⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³ is R²⁸-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³ is R²⁸-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³ is R²⁸-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R³ is R²⁸-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R³ is R²⁸-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3A) is R^(28A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(28A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(28A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(28A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(28A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(28A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(3B) is R^(28B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(28B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(28B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(28B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(28B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(28B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(3C) is R^(28C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(28C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^(28C)substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), R^(28C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(28C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(28C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(3D) is R^(28D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(28D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(28D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(28D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(28D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(28D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸. R⁵ is —C(O)-L²-R¹⁹ or —C(S)-L²-R¹⁹.R⁴ and R⁵ may optionally be joined to form

In embodiments, R⁴ and R⁵ are joined together to form:

In embodiments, L¹ is -L^(1A)-L^(1B)-, wherein L^(1A) is bonded to—C(O)— or —C(S)—. L^(1A) is a bond or —(CH₂)_(z1)—. L^(1B) is a bond,—O—, or —NR^(16B)—. In embodiments, L² is -L^(2A)-L^(2B)-, whereinL^(2A) is bonded to —C(O)— or —C(S)—. L^(2A) is a bond or —(CH₂)_(z2)—.L^(2B) is a bond, —O—, or —NR^(17B)—. The symbols z1 and z2 areindependently an integer from 1 to 10. R^(16B) and R^(17B) areindependently hydrogen or substituted or unsubstituted alkyl. Thesymbols z1 and z2 are independently an integer from 1 to 10. Inembodiments, L^(1A) is —CH₂—. In embodiments, L^(2A) is —CH₂—. Inembodiments, L^(1A) and L^(2A) are independently —CH₂—. In embodiments,L^(1A) is —CH₂—. In embodiments, L^(2A) is —CH₂—. In embodiments, L^(1B)is —O—. In embodiments, L^(2B) is —O—.

In embodiments, R⁴ has the formula:

In embodiments, R⁴ has the formula:

In embodiments, R⁴ has the formula:

In embodiments, R⁴ has the formula:

In embodiments, R⁵ has the formula:

In embodiments, R⁵ has the formula:

In embodiments, R⁵ has the formula:

In embodiments, R⁵ has the formula:

In embodiments, L^(1B) is —NR^(16B); L^(2B) is —NR^(17B); and R^(16B)and R^(17B) are independently unsubstituted C₁-C₃alkyl.

In embodiments, R⁴ is —C(O)-L¹-R¹⁸. In embodiments, R⁴ is —C(S)-L¹-R¹⁸.In embodiments, R⁵ is —C(O)-L²-R¹⁹. In embodiments, R⁵ is —C(S)-L²-R¹⁹.In embodiments, R⁴ is —C(O)-L¹-R¹⁸ and R⁵ is —C(O)-L²-R¹⁹. Inembodiments, R⁴ is —C(S)-L¹-R¹⁸ and R⁵ is —C(S)-L²-R¹⁹.

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R¹⁸ is halogen, OH, substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted aryl. In embodiments, R¹⁸ issubstituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R¹⁸ is halogen. In embodiments, R¹⁸ is OH. Inembodiments, R¹⁸ is substituted or unsubstituted phenyl. In embodiments,R¹⁸ is unsubstituted phenyl. In embodiments, R¹⁸ is Cl. In embodiments,R¹⁸ is substituted or unsubstituted C₁-C₃alkyl. In embodiments, R¹⁸ isunsubstituted C₁-C₃alkyl. In embodiments, R¹⁸ is substituted C₁-C₃alkyl.In embodiments, R¹⁸ is an unsubstituted C₃ alkyl. In embodiments, R¹⁸ isCl. In embodiments, R¹⁸ is F. In embodiments, R¹⁸ is —CH₃.

In embodiments, R¹⁹ is halogen, OH, substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted aryl. In embodiments, R¹⁹ issubstituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R¹⁹ is halogen. In embodiments, R¹⁹ issubstituted or unsubstituted phenyl. In embodiments, R¹⁹ isunsubstituted phenyl. In embodiments, R¹⁹ is Cl. In embodiments, R¹⁹ issubstituted or unsubstituted C₁-C₃alkyl. In embodiments, R¹⁹ isunsubstituted C₁-C₃alkyl. In embodiments, R¹⁹ is substituted C₁-C₃alkyl.In embodiments, R¹⁹ is an unsubstituted C₃ alkyl. In embodiments, R¹⁹ isF. In embodiments, R¹⁹ is Cl. In embodiments, R¹⁹ is —CH₃.

In embodiments, R²⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CN, —, CHO,—OR^(25A), —NR^(25B)R^(25C), —C(O)OR^(25A), —C(O)NR^(25B)R^(25C), —NO₂,—SR^(25D), —S(O)_(n25)R^(25B), —SO_(v25)NR^(25B)R^(2C),—NHNR^(25B)R^(25C), —ONR^(25B)R^(25C), —NHC(O)NHNR^(25B)R^(25C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²⁵ is R⁵⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁵-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁵-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R⁵⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁵-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR⁵⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁵ is R⁵⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁵ isR⁵⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁵ is R⁵⁵-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁵ is R⁵⁵-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁵ is R⁵⁵-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁵ is R⁵⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁵ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁵ is R⁵⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁵ is R⁵⁵-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁵ is R⁵⁵-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁵ isR⁵⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁵ is R⁵⁵-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁵ is R⁵⁵-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁵ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(25A) is R^(55A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(55A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(55A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(55A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(55A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(55A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(25B) is R^(55B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(55B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(55B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(55B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(55B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(55B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(25C) is R^(55C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(55C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(55C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(55C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(55C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(55C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(25D) is R^(55D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(55D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(55D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(55D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(55D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(55D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R²⁵ is Ring A. In embodiments, Ring A is a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, Ring A is R⁵⁵-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,Ring A is R⁵⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments, Ring A is an unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, Ring A is substituted or unsubstituted phenyl,substituted or unsubstituted pyridyl, substituted or unsubstitutedpyrazolyl, substituted or unsubstituted imidazolyl, substituted orunsubstituted oxazolyl, substituted or unsubstituted isoxazolyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedfuranyl, substituted or unsubstituted pyrrolyl, or substituted orunsubstituted thienyl. In embodiments, Ring A is substituted orunsubstituted phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, ortriazinyl.

In embodiments, R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C),R^(3A), R^(3B), R^(3C), R^(3D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A),R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B),R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B),R^(11C), R^(11D), R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B),R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B),R^(15C), R^(15D), R^(25A), R^(25B), R^(25C), R^(25D), R^(55A), R^(55B),R^(55C), and R^(55D) are independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(3A), R^(3B), R^(3C), R^(3D), R^(6A), R^(6B), R^(6C),R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D),R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D),R^(11A), R^(11B), R^(11C), R^(11D), R^(12A), R^(12B), R^(12C), R^(12D),R^(13A), R^(13B), R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D),R^(15A), R^(15B), R^(15C), R^(15D), R^(25A), R^(25B), R^(25C), R^(25D),R^(55A), R^(55B), R^(55C), and R^(55D) are independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(1B) and R^(1C), R^(2B) and R^(2C),R^(3B) and R^(3C), and R^(25B) and R^(25C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl)or substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C),R^(3A), R^(3B), R^(3C), R^(3D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A),R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B),R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B),R^(11C), R^(11D), R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B),R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B),R^(15C), R^(15D), R^(25A), R^(25B), R^(25C), R^(25D), R^(55A), R^(55B),R^(55C), and R^(55D) are independently hydrogen.

In embodiments, X¹ is CR¹⁰. In embodiments, X¹ is N. In embodiments, X²is CR¹¹. In embodiments, X² is N. In embodiments, X³ is CR¹². Inembodiments, X³ is N. In embodiments, X¹ is CR¹⁰ and X² is N and X³ isCR¹² and R⁶, R⁷ and R¹⁰ are independently hydrogen and R¹² is —OCH₃. Inembodiments, X¹ is CH and X² is N and X³ is CH and R⁶ and R⁷ areindependently hydrogen. In embodiments, X¹ is CR¹⁰ and X³ is CR¹². Inembodiments, X¹ is CH and X³ is CH. In embodiments, R¹² is —OCH₃.

In embodiments, X⁴ is N. In embodiments, X⁴ is CR¹³. In embodiments, X⁵is CR¹⁴R¹⁵. In embodiments, X⁵ is S. In embodiments, X⁵ is O. Inembodiments, X⁵ is NR_(20A). In embodiments, X⁴ is CH. In embodiments,X⁵ is CHR¹⁵. In embodiments, X⁵ is CH₂. In embodiments, X⁵ is NH.

In embodiments, X⁶ is O. In embodiments, X⁶ is O or S. In embodiments,X⁶ is NR^(23A). In embodiments, X⁶ is S. In embodiments, X⁷ is O. Inembodiments, X⁷ is O or S. In embodiments, X⁷ is NR^(24A). Inembodiments, X⁷ is S. In embodiments, X⁶ is O and X⁷ is O.

In embodiments, R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂,—SR^(6D), —SO_(n6)R^(6B), —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C),—ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁶is hydrogen.

In embodiments, R⁶ is hydrogen, halogen, —OCH₃, SO₂, SO₂—R^(6B),—OR^(6A), —NR^(6B)R^(6C), or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁶ is hydrogen. Inembodiments, R⁶ is Br. In embodiments, R⁶ is Cl. In embodiments, R⁶ isSO₂—R^(6B) wherein R^(6B) is substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁶ is SO₂—R^(6B)wherein R^(6B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁶ is SO₂—R^(6B) wherein R^(6B) is phenyl. Inembodiments, R⁶ is phenyl. In embodiments, R⁶ is —OR^(6A), whereinR^(6A) is substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁶ is —OR^(6A), wherein R^(6A)is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁶ is —OR^(6A), wherein R^(6A) is substituted orunsubstituted C₁-C₈ alkyl. In embodiments, R⁶ is —OR^(6A), whereinR^(6A) is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R⁶is —OR^(6A), wherein R^(6A) is substituted or unsubstituted C₁-C₂ alkyl.In embodiments, R⁶ is —NR^(6B)R^(6C), wherein R^(6B) and R^(6C) areunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R⁶ is —NR^(6B)R^(6C), wherein R^(6B) and R^(6C) aresubstituted or unsubstituted C₁-C₈ alkyl. In embodiments, R⁶ is—NR^(6B)R^(6C), wherein R^(6B) and R^(6C) are substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R⁶ is —NR^(6B)R^(6C), whereinR^(6B) and R^(6C) are substituted or unsubstituted C₁-C₂ alkyl.

In embodiments, R⁶ is R³⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁵-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁵-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R³⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁵-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁶ is R³⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁶ isR³⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁶ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁶ is R³⁵-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁶ is R³⁵-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁶ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁶ is R³⁵-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁶ is R³⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁶ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁶ is R³⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁶ is R³⁵-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁶ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁶ is R³⁵-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁶ is R³⁵-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁶ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁶ is R³⁵-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁶ is R³⁵-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁶ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(6A) is R^(35A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(6B) is R^(35B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(6C) is R^(35C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(6D) is R^(35D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂,—SR^(7D), —SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁷is hydrogen.

In embodiments, R⁷ is hydrogen, halogen, —OCH₃, SO₂, SO₂—R^(7B),—OR^(7A), —NR^(7B)R^(7C), or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is hydrogen. Inembodiments, R⁷ is Br. In embodiments, R⁷ is Cl. In embodiments, R⁷ isSO₂—R^(7B) wherein R^(7B) is substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is SO₂—R^(7B)wherein R^(7B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁷ is SO₂—R^(7B) wherein R^(7B) is phenyl. Inembodiments, R⁷ is phenyl. In embodiments, R⁷ is —OR^(7A), whereinR^(7A) is substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ is —OR^(7A), wherein R^(7A)is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁷ is —OR^(7A), wherein R^(7A) is substituted orunsubstituted C₁-C₈ alkyl. In embodiments, R⁷ is —OR^(7A), whereinR^(7A) is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R⁷is —OR^(7A), wherein R^(7A) is substituted or unsubstituted C₁-C₂ alkyl.In embodiments, R⁷ is —NR^(7B)R^(7C), wherein R^(7B) and R^(7C) areunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R⁷ is —NR^(7B)R^(7C), wherein R^(7B) and R^(7C) aresubstituted or unsubstituted C₁-C₈ alkyl. In embodiments, R⁷ is—NR^(7B)R^(7C), wherein R^(7B) and R^(7C) are substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R⁷ is —NR^(7B)R^(7C), whereinR^(7B) and R^(7C) are substituted or unsubstituted C₁-C₂ alkyl.

In embodiments, R⁷ is R³⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R³⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁷ is R³⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ isR³⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁷ is R³⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁷ is R³⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁷ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁷ is R³⁶-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁷ is R³⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁷ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁷ is R³⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁷ is R³⁶-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁷ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁷ is R³⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is R³⁶-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁷ is R³⁶-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁷ is R³⁶-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁷ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(7A) is R^(36A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(36A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(36A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(36A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(36A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(36A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(7B) is R^(36B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(36B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(36B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(36B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(36B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(36B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(7C) is R^(36C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(36C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(36C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(36C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(36C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(36C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(7D) is R^(36D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(36D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(36D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(36D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(36D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(36D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(8A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C), —NO₂,—SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁸ is R³⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁷-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁷-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R³⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁷-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁸ is R³⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁸ isR³⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁸ is R³⁷-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁸ is R³⁷-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁸ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁸ is R³⁷-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁸ is R³⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁸ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁸ is R³⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁸ is R³⁷-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁸ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁸ is R³⁷-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁸ is R³⁷-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁸ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁸ is R³⁷-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁸ is R³⁷-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁸ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(8A) is R^(37A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(37A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(37A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(37A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(37A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(37A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(8B) is R^(37B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(37B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(37B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(37B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(37B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(37B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(8C) is R^(37C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(37C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(37C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(37C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(37C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(37C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(8D) is R^(37D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(37D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(37D)-substituted or unsubstituted cycloalkyl (e.g., C3-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(37D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(37D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(37D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂,—SR^(9D), —SO_(n9)R^(9B), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is R³⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁸-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁸-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R³⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁸-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is R³⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁹ isR³⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁹ is R³⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁹ is R³⁸-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁹ is R³⁸-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁹ is R³⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁹ is R³⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁹ is R³⁸-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁹ is R³⁸-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁹ is R³⁸-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁹ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁹ is R³⁸-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁹ is R³⁸-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁹ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(9A) is R^(38A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(38A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(38A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(38A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(9B) is R^(38B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(38B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(38B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(38B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(9C) is R^(38C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(38C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(38C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(38C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(9D) is R^(38D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R′-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R′-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R^(38D)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), —CONR^(10B)R^(10C),—NO₂, —SR^(10D), —SO_(n10)R^(10B), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁰ is hydrogen, halogen, —OCH₃, SO₂, SO₂—R^(10B),—OR^(10A), —NR^(10B)R^(10C) or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁰ is hydrogen. Inembodiments, R′° is Br. In embodiments, R′° is Cl. In embodiments, R¹⁰is SO₂—R^(10B) wherein R^(10B) is substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁰ isSO₂—R^(10B) wherein R^(10B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R¹⁰ is SO₂—R^(10B) wherein R^(10B)is phenyl. In embodiments, R¹⁰ is phenyl. In embodiments, R¹⁰ is—OR^(10A), wherein R^(10A) is substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ is—OR^(10A), wherein R^(10A) is unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ is —OR^(10A), whereinR^(10A) is substituted or unsubstituted C₁-C₈ alkyl. In embodiments, R¹⁰is —OR^(10A), wherein R^(10A) is substituted or unsubstituted C₁-C₄alkyl. In embodiments, R¹⁰ is —OR^(10A), wherein R^(10A) is substitutedor unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁰ is —NR^(10B)R^(10C),wherein R^(10B) and R^(10C) are unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ is —NR^(10B)R^(10C),wherein R^(10B) and R^(1C) are substituted or unsubstituted C₁-C₈ alkyl.In embodiments, R¹⁰ is —NR^(10B)R^(10C), wherein R^(10B) and R^(10C) aresubstituted or unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁰ is—NR^(10B)R^(10C), wherein R^(10B) and R^(10C) are substituted orunsubstituted C₁-C₂ alkyl.

In embodiments, R¹⁰ is R³⁹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁹-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁹-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R³⁹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁹-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is R³⁹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ isR³⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁰ is R³⁹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁰ is R³⁹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁰ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁰ is R³⁹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁰ is R³⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁰ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁰ is R³⁹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁰ is R³⁹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁰ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁰ is R³⁹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁰ isR³⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁰ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁰ is R³⁹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁰ is R³⁹-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁰ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(10A) is R^(39A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(39A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(39A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(39A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(39A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(39A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(10B) is R^(39B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(39B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(39B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(39B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(39B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(39B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(10C) is R^(39C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(39C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(39C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(39C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(39C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(39C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(10D) is R^(39D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(39D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(39D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(39D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(39D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(39D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(11A), —NR^(11B)R^(11C), —COOR^(11A), —CONR^(11B)R^(11C),—NO₂, —SR^(11D), —SO_(n11)R^(11B), —SO_(v11)NR^(11B)R^(11C),—NHNR^(11B)R^(11C), —ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl); R¹⁰ and R¹¹ may optionally be joined to form a substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl) or substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R¹¹ is hydrogen, halogen, —OCH₃, SO₂, SO₂—R^(11B),—OR^(11A), —NR^(11B)R^(11C) or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹¹ is hydrogen. Inembodiments, R¹¹ is Br. In embodiments, R¹¹ is Cl. In embodiments, R¹¹is SO₂—R^(11B) wherein R^(11B) is substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹¹ isSO₂—R^(11B) wherein R^(11B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R¹¹ is SO₂—R^(11B) wherein R^(11B)is phenyl. In embodiments, R¹¹ is phenyl. In embodiments, R¹¹ is—OR^(11A), wherein R^(11A) is substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁸ is—OR^(11A), wherein R^(11A) is unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹¹ is —OR^(11A), whereinR^(11A) is substituted or unsubstituted C₁-C₈ alkyl. In embodiments, R¹¹is —OR^(11A), wherein R^(11A) is substituted or unsubstituted C₁-C₄alkyl. In embodiments, R¹¹ is —OR^(11A), wherein R^(11A) is substitutedor unsubstituted C₁-C₂ alkyl. In embodiments, R¹¹ is —NR^(11B)R^(11C),wherein R^(11B) and R^(11C) are unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹¹ is —NR^(11B)R^(11C),wherein R^(11B) and R^(11C) are substituted or unsubstituted C₁-C₈alkyl. In embodiments, R^(11B) is —NR^(11B)R^(11C), wherein R^(11B) andR^(11C) are substituted or unsubstituted C₁-C₄ alkyl. In embodiments,R¹¹ is —NR^(11B)R^(11C), wherein R^(11B) and R^(11C) are substituted orunsubstituted C₁-C₂ alkyl.

In embodiments, R¹¹ is R⁴¹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴¹-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴¹-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), 10-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴¹-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR⁴¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹¹ is R⁴¹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹¹ isR⁴¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹¹ is R⁴¹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹¹ is R⁴¹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹¹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹¹ is R⁴¹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹¹ is R⁴¹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹¹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹¹ is R⁴¹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹¹ is R⁴¹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹¹ is R⁴¹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, Cm aryl, or phenyl). In embodiments, R¹¹ is R⁴¹-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹¹ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R¹¹ is R⁴¹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹¹ is R⁴¹-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹¹ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(11A) is R^(41A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(41A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(41A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(41A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(41A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(41A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(11B) is R^(41B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(41B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(41B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(41B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(41B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(41B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(11C) is R^(41C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(41B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(41C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(41C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(41C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(41C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(11D) is R^(41D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(41D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(41D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(41D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(41D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(41D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(12A), —NR^(12B)R^(12C), —COOR^(12A), —CONR^(12B)R^(12C),—NO₂, —SR^(12D), —SO_(n12)R^(12B), —SO_(v12)NR^(12B)R^(12C),—NHNR^(12B)R^(12C), —ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R¹¹ and R¹² may optionally be joined toform a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl) or substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹² is hydrogen, halogen, —OCH₃, SO₂, SO₂—R^(12B),—OR^(12A), NR^(12B)R^(12C), or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹² is hydrogen. Inembodiments, R¹² is Br. In embodiments, R¹² is Cl. In embodiments, R¹²is SO₂—R^(12B) wherein R^(12B) is substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹² isSO₂—R^(12B) wherein R^(12B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R¹² is SO₂—R^(12B) wherein R^(12B)is phenyl. In embodiments, R¹² is phenyl. In embodiments, R¹² is—OR^(12A), wherein R^(12A) is substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹² is—OR^(12A), wherein R^(12A) is unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹² is —OR^(12A), whereinR^(12A) is substituted or unsubstituted C₁-C₈ alkyl. In embodiments, R¹²is —OR^(12A), wherein R^(12A) is substituted or unsubstituted C₁-C₄alkyl. In embodiments, R¹² is —OR^(12A), wherein R^(12A) is substitutedor unsubstituted C₁-C₂ alkyl. In embodiments, R¹² is —NR^(12B)R^(12C),wherein R^(12B) and R^(12C) are unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹² is —NR^(12B)R^(12C),wherein R^(12B) and R^(12C) are substituted or unsubstituted C₁-C₈alkyl. In embodiments, R¹² is —NR^(12B)R^(12C), wherein R^(12B) andR^(12C) are substituted or unsubstituted C₁-C₄ alkyl. In embodiments,R¹² is —NR^(12B)R^(12C), wherein R^(12B) and R^(12C) are substituted orunsubstituted C₁-C₂ alkyl.

In embodiments, R¹² is R⁴³-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴³-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴³-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R⁴³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴³-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR⁴³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹² is R⁴³-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹² isR⁴³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R^(u) is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R¹² is R⁴³-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹² is R⁴³-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹² is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹² is R⁴³-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹² is R⁴³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(1.2) is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹² is R⁴³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹² is R⁴³-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹² is R⁴³-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹² isR⁴³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹² is R⁴³-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹² is R⁴³-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹² is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(12A) is R^(43A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(43A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(43A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(43A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(43A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(43A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(12B) is R^(43B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(43B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(43B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(43B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(43B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(43B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(12C) is R^(43C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(43C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(43C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(43C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(43C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(43C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(12D) is R^(43D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(43D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(43D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(43D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(43D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(43D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R¹⁰ and R¹¹ are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula

In embodiments, R¹⁰ and R¹¹ are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹⁰ and R¹¹ are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹¹ and R¹² are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹¹ and R¹² are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹¹ and R¹² are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(13A), —NR^(13B)R^(13C), —COOR^(13A), —CONR^(13B)R^(13C),—NO₂, —SR^(13D), —SO_(n13)R^(13B), —SO_(v13)NR^(13B)R^(13C),—NHNR^(13B)R^(13C), —ONR^(13B)R^(13C), —NHC(O)NHNR^(13B)R^(13C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹³ is R⁴⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁵-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁵-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R⁴⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁵-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR⁴⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹³ is R⁴⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R^(n) isR⁴⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R^(n) is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R¹³ is R⁴⁵-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹³ is R⁴⁵-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹³ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹³ is R⁴⁵-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹³ is R⁴⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹³ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹³ is R⁴⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹³ is R⁴⁵-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹³ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹³ is R⁴⁵-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹³ isR⁴⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹³ is R⁴⁵-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹³ is R⁴⁵-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹³ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(13A) is R^(45A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(45A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(45A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(45A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(45A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(45A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(13B) is R^(45B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(45B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(45B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(45B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(45B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(45B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(13C) is R^(45C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(45C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(45C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(45C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(45C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(45C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(13D) is R^(45D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(45D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(45D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(45D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(45D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(45D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R¹⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(14A), —NR^(14B)R^(14C), —COOR^(14A), —CONR^(14B)R^(14C),—NO₂, —SR^(14D), —SO_(n14)R^(14B), —SO_(v14)NR^(14B)R^(14C),—NHNR^(14B)R^(14C), —ONR^(14B)R^(14C), —NHC(O)NHNR^(14B)R^(14C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁴ is R⁴⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R⁴⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR⁴⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁴ is R⁴⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁴ isR⁴⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁴ is R⁴⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁴ is R⁴⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁴ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁴ is R⁴⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁴ is R⁴⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁴ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁴ is R⁴⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁴ is R⁴⁶-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁴ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁴ is R⁴⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁴ isR⁴⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁴ is R⁴⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁴ is R⁴⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁴ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(14A) is R^(46A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(46A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(46A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(46A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(46A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(46A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(14B) is R^(46B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(46B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(46B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(46B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(46B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(46B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(14C) is R^(46C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(46C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(46C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(46C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(46C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(46C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(14D) is R^(46D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(46D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(45D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(46D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(46D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(45D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R¹⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(15A), —NR^(15B)R^(15C), —COOR^(15A), —CONR^(15B)R^(15C),—NO₂, —SR^(15D), —SO_(n15)R^(15B), —SO_(v15)NR^(15B)R^(15C),—NHNR^(15B)R^(15C), —ONR^(15B)R^(15C), —NHC(O)NHNR^(15B)R^(15C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁵ is R⁴⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁷-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁷-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R⁴⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁷-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR⁴⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁵ is R⁴⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁵ isR⁴⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁵ is R⁴⁷-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁵ is R⁴⁷-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁵ is R⁴⁷-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁵ is R⁴⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁵ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁵ is R⁴⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁵ is R⁴⁷-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁵ is R⁴⁷-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁵ isR⁴⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁵ is R⁴⁷-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁵ is R⁴⁷-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁵ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(15A) is R^(47A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(47A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(47A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(47A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(47A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(47A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(15B) is R^(47B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(47B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(47B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(47B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(47B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(47B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(15C) is R^(47C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(47C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(47C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(47C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(47C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(47C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(15D) is R^(47D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(47D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(47D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(47D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(47D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(47D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, L¹ is a bond, —O—, —NH—, R¹⁶-substituted orunsubstituted alkylene, R¹⁶-substituted or unsubstituted heteroalkylene.In embodiments, L² is a bond, —O—, —NH—, R¹⁷-substituted orunsubstituted alkylene, R¹⁷-substituted or unsubstituted heteroalkylene.

R¹⁶ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R²⁹-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(16B) is independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(29B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(29B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(29B)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(29B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(29B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(29B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R′⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R³²-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(17B) is independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(32B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(32B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(32B)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(32B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(32B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(32B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(17B) is independently hydrogen, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, R^(32B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(32B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(32B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(32B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(32B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(32B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(17B) is hydrogen. Inembodiments, R^(17B) is —CH₃.

R^(20A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(50A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(50A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(50A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(50A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(50A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(50A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(20A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(50A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(50A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(50A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(50A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(50A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(50A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂,—OCHF₂, R⁵¹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R⁵¹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R⁵¹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R⁵¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R⁵¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R⁵¹-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²¹ ishydrogen or halogen. In embodiments, R²¹ is F. In embodiments, R²¹ isCl.

R²² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂,—OCHI₂, —OCHF₂, R⁵²-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵²-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵²-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵²-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR⁵²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(23A) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(23A) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(53A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(53A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(53A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(53A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(53A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(53A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(24A) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(24A) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(54A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(54A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(54A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(54A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(54A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(54A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁰ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R³¹-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³¹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R³³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R³⁴-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁴-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R³⁹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R⁴⁰-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁰-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁴⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(39A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(40A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(40A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(40A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(40A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(40A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(40A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(39B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(40B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(40B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(40B)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(40B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(40B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(40B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(39C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —N,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(40C)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(40C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(40C)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(40C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(40C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(40C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(39D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(40D)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(40D)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(40D)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(40D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(40D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(40D)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴¹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R⁴²-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁴²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(41A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(42A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(42A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(42A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(42A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(42A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(42A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(41B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(42B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(42B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(42B)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(42B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(42B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(42B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(1C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(42C)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(42C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(42C)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(42C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(42C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(42C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(41D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(42D)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(42D)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(42D)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(42D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(42D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(42D)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R⁴⁴-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁴-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁴⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(43A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(44A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(44A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(44A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(44A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(44A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(44A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(43B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(44B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(44B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(44B)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(44B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(44B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(44B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(43C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(44C)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(44C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(44C)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(44C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(44C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(44C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(43D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(44D)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(44D)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(44D)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(44D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(44D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(44D)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R⁵⁶-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁶-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁵⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(55A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(56A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(56A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(56A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(56A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(56A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(56A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(55B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(56B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(56B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(56B)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(56B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(56B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(56B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(55C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(56C)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(56C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(56C)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(56C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(56C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(56C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(55D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(56D)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(56D)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(56D)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(56D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(56D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(56D)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵⁶ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, R⁵⁷-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁷-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁵⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(56A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(57A)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(57A)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(57A)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(57A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(57A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(57A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(56B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,R^(57B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(57B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(57B)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(57B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(57B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(57B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(56C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHF₂,R^(57C)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(57C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), R^(57C)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(57C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(57C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(57C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(56D) is independently oxo, halogen, —CCl₃, —CF₃, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHF₂, R^(57D)-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R^(57D)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R^(57D)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(57D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(57D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(57D)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, CI₃, —CN,—CHO, —COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.1) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.1) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R^(1.1) isR²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R^(1.1) is R²⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(1.1) is R²⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(1.1) isan unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R^(1.1) is R²⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(1.1) is R²⁶-substituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments,R^(1.1) is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(1.1) is R²⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(1.1) is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R^(1.1) is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(1.1) is R²⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(1.1) isR²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(1.1) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(1.1) is R²⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R^(1.1) is R²⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(1.1) isan unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.1A) is R^(26A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.1B) is R^(26B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.1C) is R^(26C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.1D) is R^(26D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A),—CONR^(1.2B)R^(1.2C), —NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B),—SO_(v1.2)NR^(1.2B)R^(1.2C), —NHNR^(1.2B)R^(1.2C), —ONR^(1.2B)R^(1.2C),—NHC(O)NHNR^(1.2B)R^(1.2C), substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(1.2) is —CN. In embodiments, R^(1.2) is an unsubstituted C₁-C₃ alkyl.In embodiments, R^(1.2) is hydrogen, —CN, —CHO, —OR^(1.2A),—NR^(1.2B)R^(1.2C), —C(O)OR^(1.2A), —C(O)NR^(1.2B)R^(1.2C), —NO₂,—SR^(1.2D), —S(O)_(n1)R^(1.2B), —SO_(v1)NR^(1.2B)R^(1.2C),—NHNR^(1.2B)R^(1.2C), ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.2) is hydrogen,—CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂, —C(O)OCH₃, —S(O)₂R^(1.2B), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.2) is—C(O)OR^(1.2A) wherein R^(1.2A) is substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(1.2) is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R^(1.2) is hydrogen. In embodiments, R^(1.2) is —CH₃. Inembodiments, R^(1.2) is —N(CH₃)₂. In embodiments, R^(1.2) is —CN. Inembodiments, R^(1.2) is —CH₂OCH₃. In embodiments, R^(1.2) is —C(O)OCH₃.In embodiments, R^(1.2) is —C(O)OCH₂CH₂CH₂CH₃. In embodiments, R^(1.2)is —C(O)OC(CH₃)₄. In embodiments, R^(1.2) is

In embodiments, R^(1.2) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.2) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R^(1.2) isR²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R^(1.2) is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(1.2) is R²⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(1.2) is R²⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(1.2) isan unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R^(1.2) is R²⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(1.2) is R²⁶-substituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R″2is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(1.2) is R²⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(1.2) is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R^(1.2) is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(1.2) is R²⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(1.2) isR²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(1.2) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(1.2) is R²⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R^(1.2) is R²⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(1.2) isan unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.2) is methyl substituted with substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, and R^(1.3) is CN.

In embodiments, R^(1.2A) is R^(26A) substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.2B) is R^(26B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.2C) is R^(26C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.2D) is R^(26D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A),—CONR^(1.3B)R^(1.3C), —NO₂, —SR^(13D), —SO_(n1.3)R^(1.3B),—SO_(v1.3)NR^(1.3B)R^(1.3C), —NHNR^(1.3B)R^(1.3C), —ONR^(1.3B)R^(1.3C),—NHC(O)NHNR^(1.3B)R^(1.3C) substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(1.3) is —CN. In embodiments, R^(1.3) is —CN and R^(1.2) is anunsubstituted C₁-C₃ alkyl. In embodiments, R^(1.3) is —CN and R^(1.2) ismethyl. In embodiments, R^(1.3) is hydrogen, —CN, —CHO, —OR^(1.3A),—NR^(1.3B)R^(1.3C), —C(O)OR^(1.3A), —C(O)NR^(1.3B)R^(1.3C), —NO₂,—SR^(1.3D), —S(O)_(n1)R^(1.3B), —SO_(v1)NR^(1.3B)R^(1.3C),—NHNR^(1.3B)R^(1.3C) ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.3) is hydrogen,—CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂, —C(O)OCH₃, —S(O)₂R^(1.3B), orsubstituted or unsubstituted alkyl. In embodiments, R^(1.3) is—C(O)OR^(13A) wherein R^(13A) is substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(1.3) is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R^(1.3) is hydrogen. In embodiments, R^(1.3) is —CH₃. Inembodiments, R^(1.3) is —N(CH₃)₂. In embodiments, R^(1.3) is —CN. Inembodiments, R^(1.3) is —CH₂OCH₃. In embodiments, R^(1.3) is —C(O)OCH₃.In embodiments, R^(1.3) is —C(O)OCH₂CH₂CH₂CH₃. In embodiments, R^(1.3)is —C(O)OC(CH₃)₄. In embodiments, R^(1.3) is

In embodiments, R^(1.3) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹³ is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹³ isR²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R^(1.3) is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(1.3) is R²⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(1.3) is R²⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(1.3) isan unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹³ is R²⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹³ is R²⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(1.3) is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R^(1.3) is R²⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(1.3) is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R^(1.3) is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(1.3) is R²⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(1.3) isR²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(1.3) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(1.3) is R²⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R^(1.3) is R²⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(1.3) isan unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.2) is methyl substituted with substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, and R^(1.3) is CN.

In embodiments, R^(1.3A) is R^(26A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.3B) is R^(26B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.3C) is R^(26C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.3D) is R^(26D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.4) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(1.4A), —NR^(1.4B)R^(1.4C), —COOR^(1.4A),—CONR^(1.4B)R^(1.4C), —NO₂, —SR^(1.4D), —SO_(n1.4)R^(1.4B),—SO_(v1.4)NR^(1.4B)R^(1.4C), —NHNR^(1.4B)R^(1.4C), —ONR^(1.4B)R^(1.4C),—NHC(O)NHNR^(1.4B)R^(1.4C) substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.4) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.4) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R^(1.4) isR²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R^(1.4) is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(1.4) is R²⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(1.4) is R²⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(1.4) isan unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R^(1.4) is R²⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(1.4) is R²⁶-substituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments,R^(1.4) is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(1.4) is R²⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(1.4) is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R^(1.4) is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(1.4) is R²⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(1.4) isR²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(1.4) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(1.4) is R²⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R^(1.4) is R²⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(1.4) isan unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.4A) is R^(26A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.4B) is R^(26B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.4C) is R^(26C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.4D) is R^(26D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.5) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(1.5A), —NR^(1.5B)R^(1.5C), —COOR^(1.5A),—CONR^(1.5B)R^(1.5C), —NO₂, —SR^(1.5D), —SO_(n1.5)R^(1.5B),—SO_(v1.5)NR^(1.5B)R^(1.5C), —NHNR^(1.5B)R^(1.5C), —ONR^(1.5B)R^(1.5C),—NHC(O)NHNR^(1.5B)R^(1.5C), substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.5) is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁵ is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R^(1.5) isR²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R^(1.5) is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(1.5) is R²⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(1.5) is R²⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(1.5) isan unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R^(1.5) is R²⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(1.5) is R²⁶-substituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁵is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(1.5) is R²⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(1.5) is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R^(1.5) is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(1.5) is R²⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(1.5) isR²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(1.5) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(1.5) is R²⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R^(1.5) is R²⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(1.5) isan unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1.5A) is R^(26A)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.5B) is R^(26B)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.5C) is R^(26C)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1.5) D is R^(26D)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, the compound has the formula:

wherein R⁴, R⁵, and R¹² are as described herein. In embodiments, R⁴ andR⁵ are independently —C(O)CH₃. In embodiments, R⁴ and R⁵ are both—C(O)CH₃. In embodiments, R¹² is —OCH₃. In embodiments, R⁴ and R⁵ areindependently —C(O)CH₃, —C(O)OPh, —C(O)CH₂OCH₃, C(O)NHPh, or —C(S)OPh.

In embodiments, the compound has the formula:

wherein R⁴ and R⁵ are as described herein. In embodiments, R⁴ and R⁵ areindependently —C(O)CH₃. In embodiments, R⁴ and R⁵ are both —C(O)CH₃. Inembodiments, R¹² is —OCH₃. In embodiments, R⁴ and R⁵ are independently—C(O)CH₃, —C(O)OPh, —C(O)CH₂OCH₃, C(O)NHPh, or —C(S)OPh.

In embodiments, R^(1A), R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A),R^(1.2B), R^(1.2C), R^(1.2D), R^(1.3A), R^(1.3B), R^(1.3C), R^(1.3D),R^(1.4A), R^(1.4B), R^(1.4C), R^(1.4D), R^(1.5A), R^(1.5B), R^(1.5C),R^(1.5D), R^(2A), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B),R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C),R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C),R^(11D), R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B), R^(13C),R^(13D), R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B), R^(15C),R^(15D), and R^(20A) are independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl); and R^(1.1B) and R^(1.1C), R^(1.2B) and R^(1.2C), andR^(1.3B) and R^(1.3C) substituents bonded to the same nitrogen atom mayindependently optionally be joined to form a substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl) or substituted or unsubstituted heteroaryl (e.g., 5 to10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(1.1B) and R^(1.1C), R^(1.2B) andR^(1.2C), and R^(1.3B) and R^(1.3C), R^(13B) and R^(13C), R^(14B) andR^(14C), and R^(15B) and R^(15C), R^(6B) and R^(6C), R^(7B) and R^(7C),R^(10B) and R^(10C), R^(11B) and R^(11C), and R^(12B) and R^(12C)substituents bonded to the same nitrogen atom may independentlyoptionally be joined to form a substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl) orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(1A), R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A),R^(1.2B), R^(1.2C), R^(1.2D), R^(1.3A), R^(1.3B), R^(1.3C), R^(1.3D),R^(1.4A), R^(1.4B), R^(1.4C), and R^(1.4D), R^(1.5A), R^(1.5B),R^(1.5C), and R^(1.5D), R^(2A), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A),R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B),R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B),R^(11C), R^(11D), R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B),R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B),R^(15C), R^(15D), and R^(20A) are independently hydrogen, substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

The symbols z1 and z2 are independently an integer from 1 to 10. Inembodiments, the symbols z1 and z2 are independently an integer from 1to 5. In embodiments, the symbols z1 and z2 are independently an integerfrom 1 to 3. The symbol z3 is an integer from 0 to 5. The symbols n1.2,n1.3, n1.4, n1.5, n1, n2, n3, n6, n7, n8, n9, n10, n11, n12, n13, n14,n15, and n25 are independently an integer from 0 to 4. The symbols m,v1.2, v1.3, v1.4, v1.5, v1, v2, v3, v6, v7, v8, v9, v10, v11, v12, v13,v14, v15, and v25 are independently 1 or 2. The symbol z4 is an integerfrom 0 to 2. The symbol z5 is an integer from 0 to 8.

R^(26A), R^(26B), R^(26C), R^(26D), R^(27A), R^(27B), R^(27C), R^(28A),R^(28B), R^(28C), R^(28D), R^(35A), R^(35B), R^(35C), R^(35D), R^(36A),R^(36B), R^(36C), R^(36D), R^(37A), R^(37B), R^(37C), R^(37D), R^(38A),R^(38B), R^(38C), R^(38D), R^(40A), R^(40B), R^(40C), R^(40D), R^(42A),R^(42B), R^(42C), R^(42D), R^(44A), R^(44B), R^(44C), R^(44D), R^(45A),R^(45B), R^(45C), R^(45D), R^(46A), R^(46B), R^(46C), R^(46D), R^(47A),R^(47B), R^(47C), R^(47D), R^(57A), R^(57B), R^(57C), and R^(57D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCH₁₂, unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(26A), R^(26B), R^(26C), R^(26D), R^(27A), R^(27B), R^(27C), R^(28A),R^(28B), R^(28C), R^(28D), R^(35A), R^(35B), R^(35C), R^(35D), R^(36A),R^(36B), R^(36C), R^(36D), R^(37A), R^(37B), R^(37C), R^(37D), R^(38A),R^(38B), R^(38C), R^(38D), R^(40A), R^(40B), R^(40C), R^(40D), R^(42A),R^(42B), R^(42C), R^(42D), R^(44A), R^(44B), R^(44C), R^(44D), R^(45A),R^(45B), R^(45C), R^(45D), R^(46A), R^(46B), R^(46C), R^(46D), R^(47A),R^(47B), R^(47C), R^(47D), R^(57A), R^(57B), R^(57C), and R^(57D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —COOH,—CONH₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments R^(26A), R^(26B), R^(26C), R^(26D), R^(27A), R^(27B),R^(27C), R^(28A), R^(28B), R^(28C), R^(28D), R^(35A), R^(35B), R^(35C),R^(35D), R^(36A), R^(36B), R^(36C), R^(36D), R^(37A), R^(37B), R^(37C),R^(37D), R^(38A), R^(38B), R^(38C), R^(38D), R^(40A), R^(40B), R^(40C),R^(40D), R^(42A), R^(42B), R^(42C), R^(42D), R^(44A), R^(44B), R^(44C),R^(44D), R^(45A), R^(45B), R^(45C), R^(45D), R^(46A), R^(46B), R^(46C),R^(46D), R^(47A), R^(47B), R^(47C), R^(47D), R^(57A), R^(57B), R^(57C),and R^(57D) are independently hydrogen, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(26A),R^(26B), R^(26C), R^(26D), R^(27A), R^(27B), R^(27C), R^(28A), R^(28B),R^(28C), R^(28D), R^(35A), R^(35B), R^(35C), R^(35D), R^(36A), R^(36B),R^(36C), R^(36D), R^(37A), R^(37B), R^(37C), R^(37D), R^(38A), R^(38B),R^(38C), R^(38D), R^(40A), R^(40B), R^(40C), R^(40D), R^(42A), R^(42B),R^(42C), R^(42D), R^(44A), R^(44B), R^(44C), R^(44D), R^(45A), R^(45B),R^(45C), R^(45D), R^(46A), R^(46B), R^(46C), R^(46D), R^(47A), R^(47B),R^(47C), R^(47D), R^(57A), R^(57B), R^(57C), and R^(57D) areindependently halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, -MIC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(26A), R^(26B), R^(26C), R^(26D), R^(27A), R^(27B), R^(27C), R^(28A),R^(28B), R^(28C), R^(28D), R^(35A), R^(35B), R^(35C), R^(35D), R^(36A),R^(36B), R^(36C), R^(36D), R^(37A), R^(37B), R^(37C), R^(37D), R^(38A),R^(38B), R^(38C), R^(38D), R^(40A), R^(40B), R^(40C), R^(40D), R^(42A),R^(42B), R^(42C), R^(42D), R^(44A), R^(44B), R^(44C), R^(44D), R^(45A),R^(45B), R^(45C), R^(45D), R^(46A), R^(46B), R^(46C), R^(46D), R^(47A),R^(47B), R^(47C), R^(47D), R^(57A), R^(57B), R^(57C), and R^(57D) areindependently halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —COOH, —CONH₂,unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments, R^(26A), R^(26B), R^(26C), R^(26D), R^(27A), R^(27B),R^(27C), R^(28A), R^(28B), R^(28C), R^(28D), R^(35A), R^(35B), R^(35C),R^(35D), R^(36A), R^(36B), R^(36C), R^(36D), R^(37A), R^(37B), R^(37C),R^(37D), R^(38A), R^(38B), R^(38C), R^(38D), R^(40A), R^(40B), R^(40C),R^(40D), R^(42A), R^(42B), R^(42C), R^(42D), R^(44A), R^(44B), R^(44C),R^(44D), R^(45A), R^(45B), R^(45C), R^(45D), R^(46A), R^(46B), R^(46C),R^(46D), R^(47A), R^(47B), R^(47C), R^(47D), R^(57A), R^(57B), R^(57C),and R^(57D) are independently unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R²⁶, R²⁷, R²⁸, R³⁵, R³⁶, R³⁷, R³⁸, R⁴⁰, R⁴², R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R²⁹,R^(29B), R³², R^(32B), R⁴⁸, R⁴⁹, R³¹, R³⁴, R^(50A), R⁵¹, R⁵², R^(53A),R^(54A), and R⁵⁷ are independently hydrogen, oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂,—OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R²⁶, R²⁷, R²⁸, R³⁵, R³⁶, R³⁷, R³⁸, R⁴⁰,R⁴², R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R²⁹, R^(29B), R³², R^(32B), R⁴⁸, R⁴⁹, R³¹, R³⁴,R^(50A), R⁵¹, R⁵², R^(53A), R^(54A), and R⁵⁷ are independently, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃,—OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is3. In embodiments, z1 is 4. In embodiments, z1 is 5. In embodiments, z1is 6. In embodiments, z1 is 7. In embodiments, z1 is 8. In embodiments,z1 is 9. In embodiments, z1 is 10.

In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is3. In embodiments, z2 is 4. In embodiments, z2 is 5. In embodiments, z2is 6. In embodiments, z2 is 7. In embodiments, z2 is 8. In embodiments,z2 is 9. In embodiments, z2 is 10. In embodiments, z1 and z2 areindependently an integer from 1 to 5. In embodiments, z1 and z2 areindependently an integer from 1 to 3.

In embodiments z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3is 5.

In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is2.

In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5is 5. In embodiments, z5 is 6. In embodiments, z5 is 7. In embodiments,z5 is 8.

In embodiments, n1.2 is 0. In embodiments, n1.2 is 1. In embodiments,n1.2 is 2. In embodiments, n1.2 is 3. In embodiments, n1.2 is 4. Inembodiments, n1.3 is 0. In embodiments, n1.3 is 1. In embodiments, n1.3is 2. In embodiments, n1.3 is 3. In embodiments, n1.3 is 4. Inembodiments, n1.4 is 0. In embodiments, n1.4 is 1. In embodiments, n1.4is 2. In embodiments, n1.4 is 3. In embodiments, n1.4 is 4. Inembodiments, n1.5 is 0. In embodiments, n1.5 is 1. In embodiments, n1.5is 2. In embodiments, n1.5 is 3. In embodiments, n1.5 is 4. Inembodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is 2.In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, n2 is0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2is 3. In embodiments, n2 is 4. In embodiments, n3 is 0. In embodiments,n3 is 1. In embodiments, n3 is 2. In embodiments, n3 is 3. Inembodiments, n3 is 4. In embodiments, n6 is 0. In embodiments, n6 is 1.In embodiments, n6 is 2. In embodiments, n6 is 3. In embodiments, n6 is4. In embodiments, n7 is 0. In embodiments, n7 is 1. In embodiments, n7is 2. In embodiments, n7 is 3. In embodiments, n7 is 4. In embodiments,n8 is 0. In embodiments, n8 is 1. In embodiments, n8 is 2. Inembodiments, n8 is 3. In embodiments, n8 is 4. In embodiments, n9 is 0.In embodiments, n9 is 1. In embodiments, n9 is 2. In embodiments, n9 is3. In embodiments, n9 is 4. In embodiments, n10 is 0. In embodiments,n10 is 1. In embodiments, n10 is 2. In embodiments, n10 is 3. Inembodiments, n10 is 4. In embodiments, n11 is O. In embodiments, n11is 1. In embodiments, n11 is 2. In embodiments, n11 is 3. Inembodiments, n11 is 4. In embodiments, n12 is 0. In embodiments, n12is 1. In embodiments, n12 is 2. In embodiments, n12 is 3. Inembodiments, n12 is 4. In embodiments, n13 is 0. In embodiments, n13is 1. In embodiments, n13 is 2. In embodiments, n13 is 3. Inembodiments, n13 is 4. In embodiments, n14 is 0. In embodiments, n14is 1. In embodiments, n14 is 2. In embodiments, n14 is 3. Inembodiments, n14 is 4. In embodiments, n15 is 0. In embodiments, n15is 1. In embodiments, n15 is 2. In embodiments, n15 is 3. Inembodiments, n15 is 4. In embodiments, n25 is 0. In embodiments, n25is 1. In embodiments, n25 is 2. In embodiments, n25 is 3. Inembodiments, n25 is 4.

In embodiments, m is 1. In embodiments, m is 2.

In embodiments, v1.2 is 1. In embodiments, v1.2 is 2. In embodiments,v1.3 is 1. In embodiments, v1.3 is 2. In embodiments, v1.4 is 1. Inembodiments, v1.4 is 2. In embodiments, v1.5 is 1. In embodiments, v1.5is 2. In embodiments, v1 is 1. In embodiments, v1 is 2. In embodiments,v2 is 1. In embodiments, v2 is 2. In embodiments, v3 is 1. Inembodiments, v3 is 2. In embodiments, v6 is 1. In embodiments, v6 is 2.In embodiments, v7 is 1. In embodiments, v7 is 2. In embodiments, v8is 1. In embodiments, v8 is 2. In embodiments, v9 is 1. In embodiments,v9 is 2. In embodiments, v10 is 1. In embodiments, v10 is 2. Inembodiments, v11 is 1. In embodiments, v11 is 2. In embodiments, v12is 1. In embodiments, v12 is 2. In embodiments, v13 is 1. Inembodiments, v13 is 2. In embodiments, v14 is 1. In embodiments, v14 is2. In embodiments, v15 is 1. In embodiments, v15 is 2. In embodiments,v25 is 1. In embodiments, v25 is 2.

In embodiments, the compound has the formula:

or a pharmaceutically acceptable salt thereof,wherein:R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A), —CONR^(1.2B)R^(1.2C),—NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B), —SO_(v1.2)NR^(1.2B)R^(1.2C),—NHNR^(1.2B)R^(1.2C), —ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A), —CONR^(1.3B)R^(1.3C),—NO₂, —SR^(1.3D), —SO_(n1.3)R^(1.3B), —SO_(v1.3)NR^(1.3B)R^(1.3C),—NHNR^(1.3B)R^(1.3C), —ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R^(1.4) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.4A), —NR^(1.4B)R^(1.4C), —COOR^(1.4A), —CONR^(1.4B)R^(1.4C),—NO₂, —SR^(1.4D), —SO_(n1.4)R^(1.4B), —SO_(v1.4)NR^(1.4B)R^(1.4C),—NHNR^(1.4B)R^(1.4C), —ONR^(1.4B)R^(1.4C), —NHC(O)NHNR^(1.4B)R^(1.4C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R^(1.5) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.5A), —NR^(1.5B)R^(1.5C), —COOR^(1.5A), —CONR^(1.5B)R^(1.5C),—NO₂, —SR^(1.5D), —SO_(n1.5)R^(1.5B), —SO_(v1.5)NR^(1.5B)R^(1.5C),—NHNR^(1.5B)R^(1.5C), —ONR^(1.5B)R^(1.5C), —NHC(O)NHNR^(1.5B)R^(1.5C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A), and R^(1.2B), R^(1.2C),R^(1.2D), R^(1.3A), R^(1.3B), and R^(1.3C), R^(1.3D), R^(1.4A),R^(1.4B), R^(1.4C), R^(1.4D), R^(1.5A), R^(1.5B), R^(1.5C), and R^(1.5D)are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; and R^(1.1B) and R^(1.1C), R^(1.2B) andR^(1.2C), R^(1.3B) and R^(1.3C), R^(1.4B) and R^(1.4C), and R^(1.5B) andR^(1.5C) substituents bonded to the same nitrogen atom may independentlyoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;R² is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —COOR^(2A),—CONR^(2B)R^(2C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸;R⁵ is —C(O)-L²-R¹⁹ or —C(S)-L²-R¹⁹; orR⁴ and R⁵ may optionally be joined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene;L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene;R¹⁸ and R¹⁹ are independently halogen, substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted aryl;R²⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(25A), —NR^(25B)R^(25C), —C(O)OR^(25A), —C(O)NR^(25B)R^(25C),—SR^(25D), —S(O)_(n25)R^(25B), —SO_(v25)NR^(25B)R^(25C),—NHNR^(25B)R^(25C), ONR^(25B)R^(25C), —NHC(O)NHNR^(25B)R^(25C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(3A), R^(3B),R^(3C), R^(3D), R^(25A), R^(25B), R^(25C), and R^(25D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C), and R^(25B) andR^(25C) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl;n1, n3, and n25 are independently an integer from 0 to 4;v1, v3, and v25 are independently 1 or 2;n1.2, n1.3, n1.4, and n1.5 are independently an integer from 0 to 4; andv1.2, v1.3, v1.4, and v1.5 are independently 1 or 2.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

or a pharmaceutically acceptable salt thereof,wherein:X¹ is N or CR¹⁰;X² is N or CR¹¹;X³ is N or CR¹²;R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂, —SR^(6D),—SO_(n6)R^(6B), —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C),—ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D),—SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), —CONR^(10B)R^(10C), —NO₂,—SR^(10D), —SO_(n10)R^(10B), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(11A), —NR^(11B)R^(11C), —COOR^(11A), —CONR^(11B)R^(11C), —NO₂,—SR^(11D), —SO_(n11)R^(11B), —SO_(v11)NR^(11B)R^(11C),—NHNR^(11B)R^(11C), —ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁰ and R¹¹ may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl;R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(12A), —NR^(12B)R^(12C), —COOR^(12A), —CONR^(12B)R^(12C), —NO₂,—SR^(12D), —SO_(n12)R^(12B), —SO_(v12)NR^(12B)R^(12C),—NHNR^(12B)R^(12C), —ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ and R¹² may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl;R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(10A),R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C), R^(11D), R^(12A),R^(12B), R^(12C), and R^(12D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(6B) and R^(6C), R^(7B) and R^(7C), R^(10B) and R^(10C), R^(11B) andR^(11C), and R^(12B) and R^(12C), substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;n6, n7, n10, n11 and n12 are independently an integer from 0 to 4; andv6, v7, v10, v11 and v12, are independently 1 or 2.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In some embodiments, R¹⁰ and R¹¹ or R¹¹ and R¹² are optionally joined toform a substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl having structural formula:

wherein:X⁶ is O, NR^(23A), or S;X⁷ is O, NR^(24A), or S;z4 is an integer from 0 to 2;z5 is an integer from 0 to 8;m is 1 or 2;R²¹, R²², R^(23A), and R^(24A) are independently hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

wherein:R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A), —CONR^(1.2B)R^(1.2C),—NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B), —SO_(v1.2)NR^(1.2B)R^(1.2C),—NHNR^(1.2B)R^(1.2C), —ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A), —CONR^(1.3B)R^(1.3C),—NO₂, —SR^(1.3D), —SO_(n1.3)R^(1.3B), —SO_(v1.3)NR^(1.3B)R^(1.3C),—NHNR^(1.3B)R^(1.3C), —ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;X⁴ is N or CR¹³;X⁵ is CR¹⁴R¹⁵, S, O, or NR^(20A);R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(8A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C), —NO₂, —SR^(8D),—SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂, —SR^(9D),—SO_(n9)R^(9B), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂, —SR^(9D),—SO_(n9)R^(9B), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(13A), —NR^(13B)R^(13C), —COOR^(13A), —CONR^(13B)R^(13C), NO₂,—SR^(13D), —SO_(n13)R^(13B), —SO_(v13)NR^(13B)R^(13C),—NHNR^(13B)R^(13C), —ONR^(13B)R^(13C), —NHC(O)NHNR^(13B)R^(13C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R¹⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(14A), —NR^(14B)R^(14C), —COOR^(14A), —CONR^(14B)R^(14C), —NO₂,—SR^(14D), —SO_(n14)R^(14B), —SO_(v14)NR^(14B)R^(14C),—NHNR^(14B)R^(14C), —ONR^(14B)R^(14C), —NHC(O)NHNR^(14B)R^(14C)substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R¹⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(15A), —NR^(15B)R^(15C), —COOR^(15A), —CONR^(15B)R^(15C), —NO₂,—SR^(15D), —SO_(n15)R^(15B), —SO_(v15)NR^(15B)R^(15C),—NHNR^(15B)R^(15C), —ONR^(15B)R^(15C), —NHC(O)NHNR^(15B)R^(15C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A), R^(1.2B), R^(1.2C), R^(1.2D),R^(1.3A), R^(1.3B), R^(1.3C), R^(1.3D), R^(8A), R^(8B), R^(8C), R^(8D),R^(9A), R^(9B), R^(9C), R^(9D), R^(13A), R^(13B), R^(13C), R^(13D),R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B), R^(15C), R^(15D),and R^(20A) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(1.1B) and R^(1.1C), R^(1.2B) and R^(1.2C), R^(1.3B) and R^(1.3C),R^(13B) and R^(13C), R^(14B) and R^(14C), and R^(15B) and R^(15C),substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl;n1.2, n1.3, n8, n9, n13, n14, and n15 are independently an integer from0 to 4; andv1.2, v1.3, v8, v9, v13, v14, and v15 are independently 1 or 2.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In some embodiments, R⁶ and R⁷ are independently hydrogen. In someembodiments, X² is N. In some embodiments, R¹² is —OCH₃. In someembodiments, R^(1.2) is substituted or unsubstituted alkyl.

In some embodiments, R^(1.2) is substituted or unsubstituted C₁-C₃alkyl.In some embodiments, R^(1.2) is methyl. In some embodiments, R^(1.3) is—CN. In some embodiments, R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸; and R⁵ is—C(O)-L²-R¹⁹ or —C(S)-L²-R¹⁹.

In some embodiments, R⁴ is —C(O)-L¹-R¹⁸; and R⁵ is —C(O)-L²-R¹⁹.

In some embodiments, R⁴ is —C(S)-L¹-R¹⁸; and R⁵ is —C(S)-L²-R¹⁹.

In some embodiments, L¹ and L² are independently —O—.

In some embodiments, L¹ and L² are independently —NH—.

In some embodiments, L¹ and L² are independently a bond.

In some embodiments, L¹ is -L^(1A)-L^(1B)-, wherein L^(1A) is bonded to—C(O)— or —C(S)—; and L² is -L^(2A)-L^(2B)-, wherein L^(2A) is bonded to—C(O)— or —C(S)—; L^(1A) is a bond or —(CH₂)_(z1)—; L^(1B) is a bond,—O— or —NR^(16B)—; L^(2A) is a bond or —(CH₂)_(z2)—; L^(2B) is a bond,—O— or —NR^(17B)—; z1 and z2 are independently an integer from 1 to 10;and R^(16B) and R^(17B) are independently hydrogen or substituted orunsubstituted alkyl.

In some embodiments, L^(1A) and L^(2A) are independently —CH₂—.

In some embodiments, L^(1B) is —NR^(16B); L^(2B) is —NR^(17B); andR^(16B) and R^(17B) are independently unsubstituted C₁-C₃alkyl.

In some embodiments, R¹⁸ and R¹⁹ are independently unsubstitutedC₁-C₃alkyl or unsubstituted aryl.

In some embodiments, R¹⁸ and R¹⁹ are independently unsubstituted aryl.

In some embodiments, R¹⁸ and R¹⁹ are independently halogen.

In some embodiments, R⁴ and R⁵ are joined together to form:

In some embodiments, R² is methyl.

In some embodiments, the compound or pharmaceutically acceptable saltthereof, has the structure:

In embodiments, the compound has the structure:

In embodiments, the compound has the structure:

In embodiments, the compound has the structure:

III. PHARMACEUTICAL COMPOSITIONS

In an aspect, is provided a pharmaceutical composition including acompound as described herein, or salt thereof, and a pharmaceuticallyacceptable excipient.

In an aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a combination of a compound asdescribed herein at least one additional anticancer agent.

In embodiments, the at least one additional anticancer agent includes anepigenetic inhibitor or a multi-kinase inhibitor.

In embodiments, the combination includes a first amount of the compoundand a second amount of a epigenetic inhibitor, wherein the first amountand second amount are together an effective amount to provide asynergistic therapeutic effect.

In embodiments, the combination includes a first amount of the compoundand a second amount of a multi-kinase inhibitor, wherein the firstamount and second amount are together an effective amount to provide asynergistic therapeutic effect.

In embodiments, the combination includes a first amount of the compound,a second amount of a multi-kinase inhibitor, and a third amount of aepigenetic inhibitor, wherein the first amount, the second amount, andthe third amount are together an effective amount to provide asynergistic therapeutic effect.

In embodiments, the additional anticancer agent is a multi-kinaseinhibitor. In embodiments, the multi-kinase inhibitor is sorafenib.

In embodiments, the additional anticancer agent is an epigeneticinhibitor. In embodiments, the epigenetic inhibitor is azacitidine ordecitabine. In embodiments, the epigenetic inhibitor is azacitidine. Inembodiments, the epigenetic inhibitor is decitabine.

In embodiments, the pharmaceutical composition is for use in cancer. Inembodiments, the pharmaceutical composition is for use in solid andblood tumors, including ovarian cancer, breast cancer, lung cancer,leukemia, AML, CML, lymphoma, pancreatic cancer, kidney cancer,melanoma, liver cancer, colon cancer, sarcoma, multiple myeloma, braincancer, or prostate cancer. In embodiments, the pharmaceuticalcomposition is for use in non-small cell lung cancer.

In embodiments, the compound as described herein and the multi-kinaseinhibitor or the epigenetic inhibitor are co-administered as a singledosage form.

Methods of Use

In an aspect is provided a method of treating cancer, includingadministering to a subject in need thereof a therapeutically effectiveamount of a compound as described herein, or salt thereof, includingembodiments.

In embodiments, the cancer is a solid or blood tumor.

In embodiments, the cancer is ovarian cancer, breast cancer, lungcancer, leukemia, AML, CML, lymphoma, pancreatic cancer, kidney cancer,melanoma, liver cancer, colon cancer, sarcoma, multiple myeloma, braincancer, or prostate cancer. In embodiments, the cancer is ovariancancer.

In embodiments, the method includes further including administering atleast one additional anticancer agent. In embodiments, the at least oneadditional anticancer agent includes an epigenetic inhibitor or amulti-kinase inhibitor.

In embodiments, the additional anticancer agent is a multi-kinaseinhibitor. In embodiments, the multi-kinase inhibitor is sorafenib.

In embodiments, the additional anticancer agent is an epigeneticinhibitor. In embodiments, the epigenetic inhibitor is azacitidine ordecitabine. In embodiments, the epigenetic inhibitor is azacitidine. Inembodiments, the epigenetic inhibitor is decitabine.

In embodiments, the method includes administering a first amount of thecompound and a second amount of at least one additional anticanceragent, wherein the first amount and second amount are together aneffective amount to provide a synergistic therapeutic effect.

In embodiments, the compound and the epigenetic inhibitor areco-administered as a pharmaceutical composition. In embodiments, thecompound and the multi-kinase inhibitor are co-administered as apharmaceutical composition.

In a further aspect is provided a method of inhibiting the growth of acancer cell, comprising administering to a subject in need thereof atherapeutically effective amount of a compound or composition describedherein. In embodiments, the cancer cell is an ovarian cancer cell,breast cancer cell, lung cancer cell, leukemia cell, AML cell, CML cell,lymphoma cell, pancreatic cancer cell, kidney cancer cell, melanomacell, liver cancer cell, colon cancer cell, sarcoma cell, multiplemyeloma cell, brain cancer cell, or prostate cancer cell.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

EXAMPLES Example 1. Dithio Analogs of1,4-Dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazines HavingAnticancer Activity

1,4-Dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-c]pyrazines, seecompound (I) in FIG. 1 for example, have been shown to suppresses tumorgrowth in mouse xenograft models of melanoma and lung cancer, withoutobvious signs of toxicity, following either intraperitoneal (IP) or oraladministration (PCT/US2013/066252). Additional background can be foundin the cited patent application.

Molecules of structure II as found in FIG. 1, which could be convertedin vivo to the corresponding dithiol II (R═H), mono-thio derivatives IIIor IV, or compounds of structure I (p=2), exhibit significant in vitroantitumor activity. Careful control of the substituents effectsbioavailability of the compounds, their physical properties, and therate at which the R substituent would be cleaved in vivo, whileimproving the antitumor activity relative to compound I.

Pharmaceutical compositions comprising molecules II and a pharmaceuticalacceptable expedient alone or in conjunction with another antitumoragent are of utility for treating cancer.

Four examples of compounds of structure II with R═—C(O)R or —C(O)OR′were prepared as depicted in FIG. 2 and their in vitro cytotoxicityagainst two invasive cancer cell lines, DU145 (human prostate cancer)and A2058 (human melanoma) were determined. As shown in FIG. 2,LEO-16-1833, LEO-16-1835, LEO-16-1836 showed good activity against thesetwo cancer cell lines, with LEO-16-1833 showing activity nearlyidentical to the corresponding ETP structure I (p=2).

Example 2. Synthesis and Characterization Data

Rel-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-c]pyrazine-7-carbonitrile(2) andRel-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epitrithiopyrrolo[1,2-c]pyrazine-7-carbonitrile(3). A three-neck 250 mL round bottom flask was fitted with an overheadmechanical stirrer with a grease-sealed glass fitting. The flask wascharged with 1 (2.07 g, 6.1 mmol) and S₈ (1.56 g, 6.1 mmol) and fittedwith two rubber septa. The flask was evacuated under vacuum andback-filled with Ar three times. The solids were suspended in anhydrousTHF (60 mL) and the suspension was cooled in an ice bath. After 5 min.,a solution of NaHMDS (0.6 M in PhMe, 60 mL, 36 mmol) was added over 10min with vigorous stirring. The reaction was maintained at 0° C. for 3h. The reaction was quenched with sat. aq. NH₄Cl (50 mL) and H₂O (50mL). The biphasic mixture was extracted with EtOAc (3×150 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Flash chromatography (30×250 mm of SiO₂, 5 to 10%EtOAc in CH₂Cl₂ gradient elution) afforded a 2:1 mixture of 2 and 3 (880mg, ca. 2.12 mmol, 35% yield) as an off-white solid.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)diethanethioate (4, LEO-16-1833). A mixture of 2 and 3 (53 mg, ca. 0.13mmol) was suspended in degassed THF/EtOH (1:1, 1.3 mL) under Ar. Thesuspension was cooled in an ice bath. NaBH₄ (17 mg, 0.44 mmol) was addedin 3 portions over 3 min. After 5 min, the cold bath was removed and thereaction was maintained at room temperature for 1 h. The solvent wasremoved in vacuo. The crude residue was suspended in EtOAc (2.5 mL) andK2CO₃ (35 mg, 0.25 mmol) was added. Ac₂O (30 μL, 0.32 mmol) was addedand the reaction was maintained for 17 h. The reaction was diluted withH₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.Flash chromatography (12×150 mm of SiO₂, 10% EtOAc in CH₂Cl₂) affordedbis-thioacetate 4 (60 mg, 0.12 mmol, 92% yield) as a colorless solid. ¹HNMR (500 MHz, CDCl₃): δ 6.97 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.84 (d,J=8.1 Hz, 1H), 6.00 (s, 2H), 4.86 (s, 1H), 4.34 (d, J=14.6 Hz, 1H), 3.18(s, 3H), 2.41-2.37 (m, 7H), 2.10 (s, 3H), 1.70 (s, 3H); ¹³C NMR (125MHz, CDCl₃): δ 191.9 (C), 191.8 (C), 164.9 (C), 162.8 (C), 148.3 (C),148.2 (C), 129.2 (C), 120.9 (C), 120.0 (CH), 108.8 (CH), 106.7 (CH),101.5 (CH₂), 73.6 (C), 73.2 (CH), 72.1 (C), 44.8 (CH₂), 42.4 (C), 31.6(CH₃), 31.5 (CH₃), 31.1 (CH₃), 25.3 (CH₃), 23.4 (CH₃); IR (thin film):3059, 2986, 2919, 1693, 1504, 1492, 1446, 1366, 1252, 1105 cm⁻¹; HRMS(ESI) calculated for C₂₂H₂₃N₃O₆S₂ (M-Na) 512.0926, observed 512.0909.

S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)diethanethioate (4, all S enantiomer; LEO-16-1845). 1H NMR (600 MHz,CDCl3): 6 6.97 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H),6.00 (s, 2H), 4.86 (s, 1H), 4.34 (d, J=14.6 Hz, 1H), 3.18 (s, 3H),2.41-2.37 (m, 7H), 2.10 (s, 3H), 1.70 (s, 3H); 13C NMR (125 MHz, CDCl3):6 191.9 (C), 191.8 (C), 164.9 (C), 162.8 (C), 148.3 (C), 148.2 (C),129.2 (C), 120.9 (C), 120.0 (CH), 108.8 (CH), 106.7 (CH), 101.5 (CH2),73.6 (C), 73.2 (CH), 72.1 (C), 44.8 (CH2), 42.4 (C), 31.6 (CH3), 31.5(CH3), 31.1 (CH3), 25.3 (CH3), 23.4 (CH3); IR (thin film): 3059, 2986,2919, 1693, 1504, 1492, 1446, 1366, 1252, 1105 cm−1; [α]^(22.0) D+16.3°,[α]22.1577+27.2°, [α]22.2546+30.7°, [α]22.2435+67.2° (c=0.4, CHCl3);HRMS (ESI) calculated for C22H23N3O6S2Na (M-Na) 512.0926, observed512.0909.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-isocyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)dibenzothioate (5, LEO-16-1836). Prepared in analogous fashion tocompound 4 from a mixture of 2 and 3 (51 mg, ca. 0.12 mmol) and benzoylchloride (30 μL, 0.26 mmol). Afforded 5 (48 mg, 0.079 mmol, 66% yield)as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ 7.90 (d, J=7.3 Hz, 2H),7.87 (d, J=7.3 Hz, 2H), 7.62 (app t, J=7.4 Hz, 1H), 7.55 (app t, J=7.4Hz, 1H), 7.46 (app t, J=7.7 Hz, 2H), 7.39 (app t, J=7.8 Hz, 2H), 7.01(s, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 5.98 (s, 2H),4.94 (s, 1H), 4.43 (d, J=14.8 Hz, 1H), 3.29 (s, 3H), 2.59 (d, J=14.8 Hz,1H), 2.23 (s, 3H), 1.73 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 188.35 (C),188.32 (C), 165.1 (C), 163.2 (C), 148.3 (C), 148.2 (C), 137.1 (C), 136.9(C), 134.2 (CH), 134.0 (CH), 129.2 (C), 129.0 (2CH), 128.9 (2CH), 128.0(2CH), 127.8 (2CH), 120.8 (C), 120.0 (CH), 108.8 (CH), 107.0 (CH), 101.5(CH₂), 74.0 (C), 73.4 (CH), 72.0 (C), 45.8 (CH₂), 42.4 (C), 31.4 (CH₃),25.3 (CH₃), 24.2 (CH₃); IR (thin film): 1682, 1491, 1446, 1360, 1251,1200, 1038 cm⁻¹; HRMS (ESI) calculated for C₃₂H₂₇N₃O₆S₂Na (M-Na)636.1239, observed 636.1212.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-isocyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)bis(2-phenylethanethioate) (6, LEO-16-1835). Prepared in analogousfashion to compound 4 from a mixture of 2 and 3 (53 mg, ca. 0.13 mmol)and phenylacetyl chloride (40 μL, 0.30 mmol). Afforded 6 (59 mg, 0.091mmol, 70% yield) as a colorless foam. ¹H NMR (600 MHz, CDCl₃): δ 7.39(app t, J=7.4 Hz, 2H), 7.34 (app t, J=6.7 Hz, 2H), 7.31-7.25 (m, 6H),6.91 (s, 1H), 6.82-6.79 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.03 (d, J=1.3Hz, 1H), 6.02 (d, J=1.3 Hz, 1H), 4.83 (s, 1H), 4.27 (d, J=14.6 Hz, 1H),3.88 (d, J=16.1 Hz, 1H), 3.82 (d, J=16.1 Hz, 1H), 3.74 (app s, 2H), 3.09(s, 3H), 2.36 (d, J=14.6 Hz, 1H), 2.04 (s, 3H), 1.66 (s, 3H); ¹³C NMR(125 MHz, CDCl₃): δ 193.3 (C), 193.2 (C), 164.9 (C), 162.5 (C), 148.3(C), 148.2 (C), 132.6 (C), 132.3 (C), 130.3 (2CH), 129.9 (2CH), 129.1(C), 129.0 (2CH), 128.7 (2CH), 127.9 (CH), 127.8 (CH), 120.9 (C), 120.0(CH), 108.7 (CH), 106.8 (CH), 101.5 (CH₂), 73.8 (C), 73.1 (CH), 71.8(C), 51.2 (CH₂), 50.9 (CH₂), 44.9 (CH₂), 42.3 (C), 30.9 (CH₃), 25.2(CH₃), 23.3 (CH₃); IR (thin film): 3062, 3030, 2905, 1690, 1492, 1446,1361, 1251, 1038 cm⁻¹; HRMS (ESI) calculated for C₃₄H₃₁N₃O₆S₂Na (M-Na),664.1552, observed 664.1559.

Rel-S,S′4-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-isocyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)O,O′-dimethyl bis(carbonothioate) (7, LEO-16-1837). Prepared inanalogous fashion to compound 4 from a mixture of 2 and 3 (48 mg, ca.0.12 mmol) and methyl chloroformate (20 μL, 0.26 mmol). Afforded 7 (36mg, 0.070 mmol, 57% yield) as a colorless solid. ¹H NMR (500 MHz,CDCl₃): δ 6.93 (d, J=1.3 Hz, 1H), 6.89 (dd, J=8.0, 1.3 Hz, 1H), 6.82 (d,J=8.0 Hz, 1H), 5.97 (s, 2H), 4.90 (s, 1H), 4.40 (d, J=14.7 Hz, 1H), 3.85(s, 3H), 3.79 (s, 3H), 3.16 (s, 3H), 2.42 (d, J=14.7 Hz, 1H), 2.10 (s,3H), 1.70 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.6 (C), 166.4 (C),165.2 (C), 162.8 (C), 148.3 (C), 148.2 (C), 129.0 (C), 120.8 (C), 119.9(CH), 108.7 (CH), 106.8 (CH), 101.5 (CH₂), 73.2 (CH), 72.9 (C), 70.9(C), 54.9 (CH₃), 54.8 (CH₃), 45.2 (CH₂), 42.1 (CH), 30.6 (CH₃), 25.3(CH₃), 23.9 (CH₃); IR (thin film): 2954, 1729, 1681, 1493, 1446, 1366,1130 cm⁻¹; FIRMS (ESI) calculated for C₂₂H₂₃N₃O₈S₂Na (M-Na) 544.0825,observed 544.0793.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)bis(2-chloroethanethioate) (8, LEO-1840). Disulfide 2 (40 mg, 0.10 mmol)was suspended in degassed THF/EtOH (1:1, 1.0 mL) and cooled in an icebath. Solid NaBH₄ (6.3 mg, 0.17 mmol) was added to the suspension. After5 min, the cold bath was removed and the reaction was maintained for 30min. The solvent was removed in vacuo. The residue was suspended inEtOAc (2 mL) and K₂CO₃ (32 mg, 0.23 mmol) was added. Neat chloroacetylchloride (20 μL, 0.25 mmol) was added and the reaction was maintainedfor 30 min. The solution was diluted with distilled H₂O (5 mL) andextracted with EtOAc (3×10 mL). Combined extracts were dried overNa₂SO₄, filtered, and concentrated in vacuo. Flash chromatography(12×150 mm of SiO₂, 5% to 10% EtOAc in CH₂Cl₂) afforded 8 (20 mg, 0.036mmol, 36% yield) as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ 6.93(d, J=1.2 Hz, 1H), 6.87 (dd, J=8.1, 1.2 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H),6.00 (s, 2H), 4.88 (s, 1H), 4.26 (s, 2H), 4.22 (d, J=14.6 Hz, 1H), 4.18(s, 2H), 3.19 (s, 3H), 2.47 (d, J=14.6 Hz, 1H), 2.11 (s, 3H), 1.70 (s,3H); ¹³C NMR (150 MHz, CDCl₃): P δ 190.1 (C), 189.4 (C), 164.3 (C),162.4 (C), 148.4 (2C), 128.7 (C), 120.7 (C), 120.0 (CH), 108.9 (CH),106.7 (CH), 101.6 (CH₂), 74.5 (C), 73.4 (CH), 72.5 (C), 48.3 (CH₂), 48.2(CH₂), 45.5 (CH₂), 42.4 (C), 31.3 (CH₃), 25.1 (CH₃), 23.9 (CH₃), missing1C; IR (thin film): 2989, 2939, 2253, 1688, 1365, 1251, 1038, 728 cm⁻¹;HRMS (ESI) calculated for C₂₂H₂₁C₁₂N₃O₆S₂Na (M-Na) 580.0146, observed580.0140.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)O,O′-diphenyl bis(carbonothioate) (9, LEO-16-1841). A mixture of 2 and 3(33 mg, ca. 0.082 mmol) was suspended in degassed THF/EtOH (1:1, 1 mL).The suspension was cooled in an ice bath and NaBH₄ (12.6 mg, 0.33 mmol)was added. After 5 min, the cold bath was removed and the reaction wasmaintained for 1 h. The solvent was removed in vacuo. The crude residuewas suspended in anhydrous THF (1 mL) and cooled in an ice bath. To thecooled suspension neat Et₃N (50 μL, 0.36 mmol) and phenyl chloroformate(30 μL, 0.24 mmol) were added. After 1 h, the reaction was quenched withsat aq. NaHCO₃ (2 mL) and extracted with EtOAc (3×5 mL). Combinedextracts were dried over Na₂SO₄, filtered and concentrated in vacuo.Flash chromatography ((12×150 mm of SiO₂, 2% to 5% EtOAc in CH₂Cl₂)afforded 9 (37 mg, 0.057 mmol, 69% yield) as a colorless solid. ¹H NMR(500 MHz, CDCl₃): δ 7.40 (t, J=7.7 Hz, 4H), 7.32-7.21 (m, 4H), 7.15 (d,J=7.9 Hz, 2H), 7.07 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz,1H), 6.04 (app s, 1H), 6.00 (app s, 1H), 5.00 (s, 1H), 4.49 (d, J=14.8Hz, 1H), 3.27 (s, 3H), 2.48 (d, J=14.8 Hz, 1H), 2.21 (s, 3H), 1.76 (s,3H); ¹³C NMR (125 MHz, CDCl₃): δ 165.3 (C), 165.0 (C), 164.9 (C), 162.5(C), 150.9 (C), 150.8 (C), 148.4 (C), 148.3 (C), 129.64 (2CH), 129.63(2CH), 128.9 (C), 126.7 (CH), 126.6 (CH), 121.5 (2CH), 121.2 (2CH),120.8 (C), 120.1 (CH), 108.8 (CH), 106.8 (CH), 101.5 (CH₂), 73.4 (C),73.3 (CH), 71.5 (C), 45.2 (CH₂), 42.2 (C), 30.8 (CH₃), 25.2 (CH₃), 23.9(CH₃); IR (thin film): 2922, 1742, 1688, 1490, 1362, 1252, 1183, 1160,1094, 1076 cm⁻¹; HRMS (ESI) calculated for C₃₂H₂₇N₃O₈S₂Na (M-Na)668.1137, observed 668.1145.

Rel-(4S,7S,8S,9aS)-7-(benzo[d][1,3]dioxol-5-yl)-4,8,11-trimethyl-5,10-dioxo-2-thioxotetrahydro-7H-4,9a-(epiminomethano)pyrrolo[2,1-d][1,3,5]dithiazepine-8-carbonitrile(10, LEO-16-1842). Prepared in analogous fashion to compound 9 from amixture of 2 and 3 (36 mg, ca. 0.089 mmol) and phenylchlorothionoformate (30 μL, 0.22 mmol). Afforded 10 (25 mg, 0.56 mmol,63% yield) as a yellow solid. ¹H NMR (600 MHz, CDCl₃): δ 6.83 (d, J=8.0Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 5.98 (s, 2H), 4.91 (s,1H), 3.12 (s, 3H), 3.10-3.06 (m, 2H), 1.89 (s, 3H), 1.70 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 214.0 (C), 164.6 (C), 161.4 (C), 148.7 (C),148.5 (C), 127.6 (C), 120.3 (CH), 119.9 (C), 109.0 (CH), 106.8 (CH),101.7 (CH₂), 75.0 (C), 73.6 (CH), 73.1 (C), 45.9 (CH₂), 43.2 (C), 28.7(CH₃), 25.1 (CH₃), 19.9 (CH₃); IR (thin film): 2985, 2940, 2901, 2251,1693, 1504, 1490, 1446, 1367, 1251, 1037 cm⁻¹; HRMS (ESI) calculated forC₁₉H₁₇N₃O₄S₃Na (M-Na) 470.0279, observed 470.0290.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)bis(dimethylcarbamothioate) (11, LEO-16-1843). Prepared in analogousfashion to compound 9 from a mixture of 2 and 3 (29 mg, ca. 0.072 mmol)and phenyl chlorothionoformate (20 μL, 0.22 mmol). Afforded 11 (13 mg,0.024 mmol, 33% yield) as a colorless solid. ¹H NMR (500 MHz, CDCl₃): δ7.05 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 5.97 (apps, 1H), 5.96 (app s, 1H), 4.90 (s, 1H), 4.61 (d, J=14.6 Hz, 1H), 3.21(s, 3H), 2.08-2.94 (m, 12H), 2.37 (d, J=14.6 Hz, 1H), 2.10 (s, 3H), 1.69(s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 165.4 (C), 163.89 (C), 163.88 (C),163.7 (C), 148.1 (C), 148.0 (C), 129.7 (C), 121.0 (C), 120.2 (CH), 108.6(CH), 107.0 (CH), 101.3 (CH₂), 73.5 (C), 73.3 (CH), 71.8 (C), 45.3(CH₂), 42.2 (C), 37.2 (CH₃), 31.0 (2CH₃), 29.8 (2CH₃), 25.4 (CH₃), 24.4(CH₃); IR (thin film): 2933, 2237, 1681, 1359, 1252, 1097, 1036 cm⁻¹;FIRMS (ESI) calculated for C₂₄H₂₉N₅O₆S₂Na (M-Na) 570.1457, observed570.1443.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)bis(2-methoxyethanethioate) (12, LEO-16-1844). A mixture of 2 and 3 (33mg, ca. 0.080 mmol) was suspended in degassed THF/EtOH (1:1, 1 mL). Thesuspension was cooled in an ice bath and NaBH₄ (12.1 mg, 0.32 mmol) wasadded. After 5 min, the cold bath was removed and the reaction wasmaintained for 1.5 h. The solvent was removed in vacuo. The cruderesidue was suspended in anhydrous THF (1 mL) and cooled in a −78° C.bath. To the cooled suspension neat Et₃N (40 μL, 0.29 mmol) and2-methoxyacetyl chloride (20 μL, 0.22 mmol) were added. After 1 h, thereaction was quenched with sat aq. NaHCO₃ (2 mL) and extracted withEtOAc (3×5 mL). Combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. Flash chromatography (12×150 mm of SiO₂, 2% to 5%EtOAc in CH₂Cl₂) afforded 12 (26 mg, 0.047 mmol, 58% yield) as acolorless solid. ¹H NMR (500 MHz, CDCl₃): δ 6.97 (s, 1H), 6.88 (d, J=8.0Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 5.98 (S, 2H), 4.88 (S, 1H), 4.34 (d,J=14.7 Hz, 1H), 4.15 (d, J=16.3 Hz, 1H), 4.13-4.01 (m, 3H), 3.54 (s,3H), 3.49 (s, 3H), 3.16 (s, 3H), 2.44 (d, J=14.7 Hz, 1H), 2.09 (s, 3H),1.70 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 196.18 (C), 196.17 (C), 165.0(C), 162.9 (C), 148.3 (C), 148.2 (C), 129.2 (C), 121.0 (C), 120.0 (CH),108.7 (CH), 106.7 (CH), 101.5 (CH₂), 77.8 (CH₂), 77.7 (CH₂), 73.3 (C),73.1 (CH), 71.1 (C), 60.44 (CH₃), 60.43 (CH₃), 44.9 (CH₂), 42.3 (C),31.0 (CH₂), 25.3 (CH₃), 23.8 (CH₃); IR (thin film): 2992, 2935, 2830,2253, 1693, 1492, 1446, 1364, 1251, 1196, 1123, 1038 cm⁻¹; FIRMS (ESI)calculated for C₂₄H₂₇N₃O₈S₂Na (M-Na) 572.1137, observed 572.1130.

EthylRel-(2S,4R,5S)-4-cyano-5-(6-methoxypyridin-3-yl)-4-methylpyrrolidine-2-carboxylate(14) and ethylRel-(2S,4S,5S)-4-cyano-5-(6-methoxypyridin-3-yl)-4-methylpyrrolidine-2-carboxylate(15). A 100 mL round-bottom flask was charged with2-methoxypyridine-5-carbaldehyde (13, 1.33 g, 9.92 mmol) and glycineethyl ester hydrochloride (1.66 g, 11.9 mmol) and MeCN (20 mL). To thesuspension was added Et₃N (1.5 mL, 10.8 mmol) and the mixture wasstirred vigorously for 16 h. The solvent was removed in vacuo and thecrude residue was diluted with H₂O (20 mL) and extracted with CH₂Cl₂(3×20 mL). Combined organic extracts were dried over Na₂SO₄, filteredthrough cotton, and concentrated in vacuo. The crude imine (2.11 g, 9.49mmol, 96% yield) was dissolved in anhydrous THF (16 mL) under Ar. To thesuspension was added LiBr (990 mg, 11.4 mmol) and Et₃N (1.6 mL, 11.5mmol). After 2 min, methacrylonitrile (1.2 mL, 14.3 mmol) was added tothe solution and the reaction was maintained for 16 h. The reaction wasconcentrated in vacuo. The residue was diluted with brine (20 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried over Na₂SO₄, filtered through cotton, and concentrated in vacuo.Flash chromatography (28×250 mm of SiO₂, 20% to 50% EtOAc in hexanes)afforded pyrrolidine ester 14 (300 mg, 1.04 mmol, 11% yield) as acolorless solid and pyrrolidine ester 15 (1.74 g, 6.01 mmol, 63% yield)as a pale yellow oil. Data for 14: ¹H NMR (600 MHz, CDCl₃): δ 8.24 (d,J=2.5 Hz, 1H), 7.70 (dd, J=8.6, 2.5 Hz, 1H), 6.76 (d, J=8.7 Hz, 1H),4.54 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (app t, J=7.3 Hz, 1H), 3.94(s, 3H), 2.75 (dd, J=13.5, 9.7 Hz, 1H), 2.60 (br s, 1H), 2.25 (dd,J=13.5, 6.1 Hz, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.03 (s, 3H); ¹³C NMR (125MHz, CDCl₃): δ 173.0 (C), 164.5 (C), 145.9 (CH), 137.8 (CH), 125.1 (C),123.8 (C), 110.9 (CH), 67.3 (CH), 61.7 (CH₂), 57.2 (CH), 53.7 (CH₃),41.5 (CH₂), 40.2 (C), 20.5 (CH₃), 14.3 (CH₃); IR (thin film): 3344,2983, 2947, 2904, 2850, 2235, 1737, 1608, 1495, 1285, 1202, 1028 cm⁻¹;FIRMS (ESI) calculated for C₁₅H₁₉N₃O₃ (M-Na) 312.1324, observed312.1316. Data for 15: ¹H NMR (600 MHz, CDCl₃): δ 8.12 (d, J=2.5 Hz,1H), 7.96 (dd, J=8.6, 2.5 Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 4.33-4.23 (m,2H), 3.97 (dd, J=9.7, 4.1 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 1H), 2.83 (dd,J=13.7, 4.1 Hz, 1H), 2.69 (br s, 1H), 2.28 (dd, J=13.7, 9.7 Hz, 1H),1.40 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 172.9(C), 164.9 (C), 146.5 (CH), 137.7 (CH), 125.1 (C), 121.9 (C), 111.3(CH), 69.7 (CH), 61.8 (CH₂), 57.3 (CH), 53.7 (CH₃), 43.8 (C), 42.1(CH₂), 21.9 (CH₃), 14.3 (CH₃); IR (thin film): 3346, 2981, 2948, 2904,2878, 2850, 2235, 1736, 1609, 1495, 1285, 1205, 1028 cm⁻¹; HRMS (ESI)calculated for C₁₅H₁₉N₃O₃ (M-Na) 312.1324, observed 312.1329.

Rel-(3R,6S,7S,8aS)-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-c]pyrazine-7-carbonitrile(16). In a 100 mL round bottom flask, pyrrolidine ester 15 (1.28 g, 4.42mmol) was dissolved in anhydrous CH₂Cl₂ (15 mL). The solution was cooledin an ice bath. To the solution was added Et₃N (740 μL, 5.3 mmol) and2-chloropropionyl chloride (470 μL, 4.9 mmol). The reaction wasmaintained for 1 h, by which time starting material had been consumed(by TLC). The reaction was quenched with H₂O (10 mL) and the biphasicmixture was stirred vigorously for 10 min. The biphasic mixture wasextracted with CH₂Cl₂ (3×20 mL). The organic layer was concentrated invacuo. The crude residue was dissolved in CH₂Cl₂ (20 mL) and a solutionof MeNH₂ (40% in H₂O) and the biphasic mixture was stirred vigorouslyfor 12 h. The mixture was extracted with CH₂Cl₂ (3×20 mL). Combinedextracts were dried over Na₂SO₄, filtered through cotton, andconcentrated in vacuo to afford a yellow foam. The residue was dissolvedin CH₂Cl₂ (10 mL) and MeOH (10 mL). The solution was stirred under astream of air until ca. 4 mL of solution remained. The suspension wascooled in the freezer for 18 h. Filtration afforded diketopiperazine 16(490 mg, 1.50 mmol, 34% yield as a colorless solid. ¹H NMR (600 MHz,CDCl₃): δ 7.97 (d, J=2.6 Hz, 1H), 7.37 (dd, J=8.6, 2.6 Hz, 1H), 6.76 (d,J=8.6 Hz, 1H), 4.87 (s, 1H), 4.37 (dd, J=11.3, 6.6 Hz, 1H), 3.92 (s,3H), 3.89 (q, J=7.3 Hz, 1H), 3.03 (s, 3H), 2.77 (dd, J=13.4, 11.4 Hz,1H), 2.50 (dd, J=13.4, 6.6 Hz, 1H), 1.69 (s, 3H), 1.48 (d, J=7.3 Hz,3H); ¹³C NMR (125 MHz, CDCl₃): δ 166.8 (C), 165.9 (C), 164.7 (C), 144.8(CH), 136.9 (CH), 125.4 (C), 119.9 (C), 111.5 (CH), 67.4 (CH), 60.9(CH), 56.2 (CH), 53.7 (CH₃), 42.5 (C), 36.9 (CH₂), 32.2 (CH₃), 25.1(CH₃), 15.5 (CH₃); IR (thin film): 2983, 2946, 2245, 1673, 1609, 1494,1402, 1288, 1026 cm⁻¹; HRMS (ESI) calculated for C₁₇H₂₀N₄O₃Na (M-Na)351.1433, observed 351.1430.

Rel-(3S,6S,7S,8aS)-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-c]pyrazine-7-carbonitrile(17) andRel-(3S,6S,7S,8aS)-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epitrithiopyrrolo[1,2-c]pyrazine-7-carbonitrile(18). A 25 mL round bottom flask was charged with diketopiperazine 16(120 mg, 0.37 mmol) and S₈ (100 mg, 0.39 mmol) and anhydrous THF (3.7mL) under Ar. The suspension was cooled in an ice bath. A solution ofNaHMDS (0.6 M in PhMe, 3.7 mL, 2.2 mmol) was added over 2 min. Thereaction was maintained for 2 h and quenched with saturated aqueousNH₄Cl (5 mL). The mixture was extracted with EtOAc (3×10 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Flash chromatography (30×250 mm of SiO₂, 5% to10% acetone in CH₂Cl₂) afforded a mixture of 17 and 18 (68 mg, 0.17mmol, ca. 47% yield) as a yellow solid. Data for 17: ¹H NMR (600 MHz,CDCl₃): δ 8.16 (d, J=2.4 Hz, 1H), 7.64 (dd, J=8.6, 2.4 Hz, 1H), 6.84 (d,J=8.6 Hz, 1H), 4.86 (s, 1H), 3.96 (s, 3H), 3.31 (d, J=15.0 Hz, 1H), 3.08(s, 3H), 3.00 (d, J=15.0 Hz, 1H), 1.94 (s, 3H), 1.69 (s, 3H); ¹³C NMR(125 MHz, CDCl₃): δ 165.5 (C), 165.0 (C), 162.1 (C), 145.5 (CH), 137.3(CH), 122.5 (C), 120.2 (C), 111.7 (CH), 73.44 (C), 73.43 (C), 69.9 (CH),53.8 (CH₃), 44.4 (C), 42.9 (CH₂), 27.9 (CH₃), 24.4 (CH₃), 18.2 (CH₃); IR(thin film): 2985, 2947, 2903, 2251, 1694, 1610, 1496, 1359, 1288, 1026cm⁻¹; HRMS (ESI) calculated for C₁₇H₁₈N₄O₃S₂Na (M-Na) 413.0718, observed413.0716.

Rel-S,S′-((3S,6S,7S,8aS)-7-cyano-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)diethanethioate (19, LEO-16-1839). Prepared in analogous fashion tocompound 5 from a mixture of 17 and 18 (52 mg, ca. 0.13 mmol) and aceticanhydride (40 μL, 0.42 mmol). Afforded 18 (37 mg, 0.078 mmol, 58% yield)as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ 8.25 (d, J=2.5 Hz, 1H),7.76 (dd, J=8.6, 2.5 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 4.90 (s, 1H), 4.39(d, J=14.6 Hz, 1H), 3.96 (s, 3H), 3.17 (s, 3H), 2.42 (d, J=14.6 Hz, 1H),2.40 (s, 3H), 2.35 (s, 3H), 2.08 (s, 3H), 1.69 (s, 3H); ¹³C NMR (150MHz, CDCl₃): δ 191.9 (C), 191.7 (C), 164.8 (C), 164.7 (C), 162.8 (C),145.5 (CH), 137.0 (CH), 124.0 (C), 120.8 (C), 111.5 (CH), 73.6 (C), 72.0(C), 71.1 (CH), 53.8 (CH₃), 44.7 (CH₂), 42.3 (C), 31.50 (CH₃), 31.48(CH₃), 31.0 (CH₃), 25.1 (CH₃), 23.7 (CH₃); IR (thin film): 2980, 2923,2850, 2361, 1686, 1610, 1496, 1365, 1288, 1109 cm⁻¹; HRMS (ESI)calculated for C₂₁H₂₄N₄O₅S₂Na (M-Na) 499.1086, observed 499.1077.

Rel-S,S′-((3S,6S,7S,8aS)-7-cyano-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-c]pyrazine-3,8a(6H)-diyl)O,O′-dimethyl bis(carbonothioate) (20, LEO-16-1857). Prepared inanalogous fashion to compound 7 from a mixture of 17 and 18 (55 mg, 0.14mmol) and methyl chloroformate (30 μL, 0.39 mmol). Afforded 20 (44 mg,0.087 mmol, 61% yield) as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ8.22 (d, J=2.5 Hz, 1H), 7.77 (dd, J=8.7, 2.5 Hz, 1H), 6.80 (d, J=8.7 Hz,1H), 4.94 (s, 1H), 4.45 (d, J=14.8 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H),3.78 (s, 3H), 3.16 (s, 3H), 2.45 (d, J=14.8 Hz, 1H), 2.09 (s, 3H), 1.70(s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ166.5 (C), 166.4 (C), 165.1 (C),164.7 (C), 163.0 (C), 145.6 (CH), 136.9 (CH), 123.9 (C), 120.7 (C),111.5 (CH), 72.9 (C), 71.2 (CH), 70.9 (C), 55.0 (CH₃), 54.8 (CH₃), 53.7(CH₃), 45.1 (CH₂), 42.0 (C), 30.6 (CH₃), 25.0 (CH₃), 24.1 (CH₃); IR(thin film): 2984, 2954, 2255, 1731, 1688, 1496, 1366, 1289, 1190, 1129cm⁻¹; HRMS (ESI) calculated for C₂₁H₂₄N₄O₇S₂Na (M-Na) 531.0984, observed531.1003.

Rel-(4S,7S,8S,9aS)-7-(6-methoxypyridin-3-yl)-4,8,11-trimethyl-5,10-dioxo-2-thioxotetrahydro-7H-4,9a-(epiminomethano)pyrrolo[2,1-d][1,3,5]dithiazepine-8-carbonitrile(21, LEO-16-1858). Prepared in analogous fashion to compound 9 from amixture of 17 and 18 (54 mg, ca. 0.14 mmol) and phenylchlorothionoformate (30 μL, 0.22 mmol). Afforded 21 (22 mg, 0.56 mmol,36% yield) as a yellow solid. ¹H NMR (600 MHz, CDCl₃): δ 8.15 (d, J=2.5Hz, 1H), 7.49 (dd, J=8.7, 2.5 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.01 (s,1H), 3.99 (s, 3H), 3.18-3.14 (m, 5H), 1.94 (s, 3H), 1.76 (s, 3H); ¹³CNMR (150 MHz, CDCl₃): δ 213.7 (C), 165.0 (C), 164.5 (C), 161.5 (C),145.6 (CH), 136.7 (CH), 122.6 (C), 119.7 (C), 112.0 (CH), 75.0 (C), 73.0(C), 71.3 (CH), 53.9 (CH₃), 45.8 (CH₂), 43.0 (C), 28.7 (CH₃), 24.7(CH₃), 19.9 (CH₃); IR (thin film): 2985, 2946, 2240, 1690, 1495, 1369,1288, 1002, 731 cm⁻¹; HRMS (ESI) calculated for C₁₈H₁₈N₄O₃S₃Na (M-Na)457.0439, observed 457.0425.

Leo-16-1862 v(R, S, S, S)-enantiomer. 1H NMR (600 MHz, CDCl3): 6 7.11(d, J=1.9 Hz, 1H), 7.00 (dd, J=8.1, 1.9 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H),6.06 (s, br, 1H), 5.07 (s, 1H), 4.33 (d, J=14.3 Hz, 1H), 3.77-3.73 (m,4H), 3.25 (s, 3H), 2.96 (d, J=14.1 Hz, 1H), 2.83 (d, J=14.1 Hz, 1H),2.76-2.72 (m, 4H), 2.56 (d, J=14.3 Hz, 1H), 2.48 (s, 3H), 2.43 (s, 3H),2.16 (s, 3H). HRMS (ESI) calculated for C₂₆H₃₀N₄O₇S₂Na (M-Na) 597.1454,observed 597.1446.

Leo-16-1866 (racemate). 1H NMR (600 MHz, CDCl3): 6 8.36 (d, J=2.5 Hz,1H), 7.92 (dd, J=8.7, 12.5 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.15 (s,1H), 4.36 (d, J=14.5 Hz, 1H),4.01 (s, 3H), 3.76-3.73 (m, 4H), 3.23 (s,3H), 2.90 (d, J=14.0 Hz, 1H), 2.86 (d, J=14.0 Hz, 1H), 2.73-2.71 (m,4H), 2.56 (d, J=14.5 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H).HRMS (ESI) calculated for C₂₅H₃₁N₅O₆S₂Na (M-Na) 584.1614, observed584.1619.

Leo-16-1867 (racemate). 1H NMR (600 MHz, CDCl3): 6 8.36 (d, J=2.5 Hz,1H), 7.91 (dd, J=8.8, 2.5 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 5.15 (s, 1H),4.35 (d, J=14.0 Hz, 1H), 4.01 (s, 3H), 3.51-3.46 (m, 4H), 3.23 (s, 3H),2.91 (d, J=13.8 Hz, 1H), 2.88 (d, J=13.8 Hz, 1H), 2.69-2.64 (m, 4H),2.56 (d, J=14.0 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.13 (s, 3H), 1.51(s, 9H). HRMS (ESI) calculated for _(C30H40N6O7S2Na) (M-Na) 683.2297,observed 683.2299.

Leo-16-1868 (racemate). 1H NMR (600 MHz, CDCl3): 6 8.66 (d, J=2.7 Hz,1H), 8.05 (dd, J=8.3, 2.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 5.25 (s, 1H),4.40 (d, J=14.6 Hz, 1H), 3.79-3.74 (m, 4H), 3.23 (s, 3H), 2.91 (d,J=14.7 Hz, 1H), 2.88 (d, J=14.7 Hz, 1H), 2.74-2.70 (m, 4H), 2.54 (d,J=14.6 Hz, 1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H). HRMS (ESI)calculated for C₂₄H₂₈ClN₅O₅S₂Na (M-Na) 588.1118, observed 588.1125.

Leo-16-1869 (racemate). 1H NMR (600 MHz, CDCl3): 6 8.28 (d, J=2.8 Hz,1H), 8.04 (dd, J=8.5, 2.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 5.25 (s, 1H),4.39 (d, J=14.7 Hz, 1H), 3.52-3.46 (m, 4H), 3.22 (s, 3H), 2.90 (t,J=13.9 Hz, 2H), 2.68-2.64 (m, 4H), 2.53 (d, J=14.7 Hz, 1H), 2.45 (s,3H), 2.42 (s, 3H), 2.13 (s, 3H), 2.10 (s, 9H). HRMS (ESI) calculated forC₂₉H₃₇ClN₆O₆S₂Na (M-Na) 687.1802, observed 687.1811.

Leo-17-1876 (S, R, R, R)-enantiomer). 1H NMR (600 MHz, CDCl3): 6 7.10(d, J=1.9 Hz, 1H), 6.98 (dd, J=8.0, 1.9 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H),6.05 (d, J=1.6 Hz, 1H), 6.04 (d, J=1.6 Hz, 1H), 5.06 (s, 1H), 4.31 (d,J=14.8 Hz, 1H), 3.48-3.46 (m, 4H), 3.24 (s, 3H), 2.95 (d, J=13.7 Hz,1H), 2.84 (d, J=13.7 Hz, 1H), 2.69-2.66 (m, 4H), 2.55 (d, J=14.8 Hz,1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.14 (s, 3H), 1.50 (s, 9H). HRMS (ESI)calculated for C₃₁H₃₉N₅O₈S₂Na (M-Na) 696.2138, observed 696.2135.

Example 3. Inhibition of Cutaneous T-Cell Lymphoma (CTCL) in Mice byS,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)diethanethioate

NSG (NOD. Cg-Prkdcscid II2rgtm1Wjl/SzJ) mice (5 to 7 weeks of age) wereobtained from an-animal in-house breeding facility. The facility micestock derived from mice obtained from Jackson Laboratory. All animalexperiments were conducted in accordance with protocol approved by theCity of Hope Beckman Research Institute IACUC.

CTCL tumor model: 3 million of Hut 78 cells in 100 μl (cells inPBS:Matrigel=1:1) injected subcutaneously.

The compound stock of 60 mg/ml was made in DMSO and diluted to 2 mg/mlin 30% Solutol. The compound was administered orally (by gavage) at 10μl per gram of mice body weight in a dose of 20 mg/kg for 3 consecutivedays/week.

100 μl of 3×10⁶ Hut78 cells were injected subcutaneously into mice leftflanks. The treatments were initiated when the tumor size reachedapproximately 200 mm³. The compound or the vehicle alone wereadministered for 3 consecutive days/week.

The obtained results have shown a significant effect of the compound onthe mice tumor size. The data demonstrated 86.5% inhibition of the tumorsize after the treatment with the compound.

EMBODIMENTS

Embodiment P1. A compound having the formula:

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(1A), —NR^(1B)R^(1C), —C(O)OR^(1A),        —C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D), —S(O)_(n1)R^(1B),        —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),        —NHC(O)NHNR^(1B)R^(1C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —COOR^(2A),        —CONR^(2B)R^(2C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C),        —NO₂, —SR^(3D), —SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C),        —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸;    -   R⁵ is —C(O)-L²-R¹⁹ or —C(S)-L²-R¹⁹; or    -   R⁴ and R⁵ may optionally be joined to form

-   -   L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   R¹⁸ and R¹⁹ are independently halogen, substituted or        unsubstituted C₁-C₃alkyl, substituted or unsubstituted aryl;    -   R²⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(25A), —NR^(25B)R^(25C), —C(O)OR^(25A),        —C(O)NR^(25B)R^(25C), —NO₂, —SR^(25D), —S(O)_(n25)R^(25B),        —SO_(v25)NR^(25B)R^(25C), —NHNR^(25B)R^(25C), ONR^(25B)R^(25C),        —NHC(O)NHNR^(25B)R^(25C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(3A),        R^(3B), R^(3C), R^(3D), R^(25A), R^(25B), R^(25C), and R^(25D)        are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,        —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,        —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,        —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,        —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; and R^(1B) and R^(1C),        R^(2B) and R^(2C), R^(3B) and R^(3C), and R^(25B) and R^(25C)        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl;    -   z3 is an integer from 0 to 5;    -   n1, n3, and n25 are independently an integer from 0 to 4; and    -   v1, v3, and v25 are independently 1 or 2.

Embodiment P2. The compound of embodiment P1, wherein the compound hasthe formula:

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   X¹ is N or CR¹⁰;    -   X² is N or CR¹¹;    -   X³ is N or CR¹²;    -   R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C),        —NO₂, —SR^(6D), —SO_(n6)R^(6B), —SO_(v6)NR^(6B)R^(6C),        —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C),        —NO₂, —SR^(7D), —SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C),        —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(10A), —NR^(10B)R^(10C), —COOR^(10A),        —CONR^(10B)R^(10C), —NO₂, —SR^(10D), —SO_(n10)R^(10B),        —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),        —NHC(O)NHNR^(10B)R^(10C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(11A), —NR^(11B)R^(11C), —COOR^(11A),        —CONR^(11B)R^(11C), —NO₂, —SR^(11D), —SO_(n11)R^(11B),        —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C), —ONR^(11B)R^(11C),        —NHC(O)NHNR^(11B)R^(11C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R¹⁰ and R¹¹ may        optionally be joined to form a substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl;    -   R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(12A), —NR^(12B)R^(12C), —COOR^(12A),        —CONR^(12B)R^(12C), —NO₂, —SR^(12D), —SO_(n12)R^(12B),        —SO_(v12)NR^(12B)R^(12C), —NHNR^(12B)R^(12C), —ONR^(12B)R^(12C),        —NHC(O)NHNR^(12B)R^(12C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R″ and R¹² may        optionally be joined to form a substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl;    -   R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D),        R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C),        R^(11D), R^(12A), R^(12B), R^(12C), and R^(12D) are        independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂,        —OCHI₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl; and R^(6B) and R^(6C), R^(7B) and        R^(7C), R^(10B) and R^(10C), R^(11B) and R^(11C), and R^(12B)        and R^(12C), substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl;    -   n6, n7, n10, n11 and n12 are independently an integer from 0 to        4; and    -   v6, v7, v10, v11 and v12, are independently 1 or 2.

Embodiment P3. The compound of embodiment P2, wherein the compound hasstructural formula:

-   -   wherein:    -   R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A),        —CONR^(1.2B)R^(1.2C), —NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B),        —SO_(v1.2)NR^(1.2B)R^(1.2C), —NHNR^(1.2B)R^(1.2C),        —ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A),        —CONR^(1.3B)R^(1.3C), —NO₂, —SR^(1.3D), —SO_(n1.3)R^(1.3B),        —SO_(v1.3)NR^(1.3B)R^(1.3C), —NHNR^(1.3B)R^(1.3)C,        —ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.4) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.4A), —NR^(1.4B)R^(1.4C), —COOR^(1.4A),        —CONR^(1.4B)R^(1.4C), —NO₂, —SR^(1.4D), —SO_(n1.4)R^(1.4B),        —SO_(v1.4)NR^(1.4B)R^(1.4C), —NHNR^(1.4B)R^(1.4)C,        —ONR^(1.4B)R^(1.4C), —NHC(O)NHNR^(1.4B)R^(1.4C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.5) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.5A), —NR^(1.5B)R^(1.5C), —COOR^(1.5A),        —CONR^(1.5B)R^(1.5C), —NO₂, —SR^(1.5D), —SO_(n1.5)R^(1.5B),        —SO_(v1.5) NR^(1.5B)R^(1.5C), —NHNR^(1.5B)R^(1.5C),        —ONR^(1.5B)R^(1.5C), —NHC(O)NHNR^(1.5B)R^(1.5C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A), R^(1.2B), R^(1.2C),        R^(1.2D), R^(1.3A), R^(1.3)B, R^(1.3C), R^(1.3D), R^(1.4A),        R^(1.4B), R^(1.4C), R^(1.4D), R^(1.5A), R^(1.5B), R^(1.5C), and        R^(1.5D) are independently hydrogen, halogen, —CF₃, —CCl₃,        —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,        —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,        —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,        —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; and R^(1.1B) and        R^(1.1C), R^(1.2B) and R^(1.2C), R^(1.3B) and R^(1.3C), R^(1.4B)        and R^(1.4C), and R^(1.5B) and R^(1.5C) substituents bonded to        the same nitrogen atom may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl or substituted or        unsubstituted heteroaryl;    -   n1.2, n1.3, n1.4, and n1.5 are independently an integer from 0        to 4; and        v1.2, v1.3, v1.4, and v1.5 are independently 1 or 2.

Embodiment P4. The compound of embodiment P3, wherein the compound hasstructural formula:

Embodiment P5. The compound of any one of embodiments P2 to P4, whereinR¹⁰ and R¹¹ or R¹¹ and R¹² are optionally joined to form a substitutedor unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

-   -   wherein:    -   X⁶ is O, NR^(23A), or S;    -   X⁷ is O, NR^(24A), or S;    -   z4 is an integer from 0 to 2;    -   z5 is an integer from 0 to 8;    -   m is 1 or 2;    -   R²¹; R²²; R^(23A), and R^(24A) are independently hydrogen,        halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,        —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂,        —OCHF₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.

Embodiment P6. The compound of embodiments P3 or P4, wherein thecompound has the formula:

Embodiment P7. The compound of embodiment P5, wherein the compound hasthe formula:

Embodiment P8. The compound of embodiment P7, wherein the compound hasthe formula:

Embodiment P9. The compound of embodiment P5, wherein the compound hasthe formula:

Embodiment P10. The compound of embodiment P9, wherein the compound hasformula:

Embodiment P11. The compound of embodiment P5, wherein the compound hasthe formula:

Embodiment P12. The compound of embodiment P11, wherein the compound hasformula:

Embodiment P13. The compound of embodiment P1, wherein the compound hasstructural formula:

-   -   wherein:    -   R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A),        —CONR^(1.2B)R^(1.2C), —NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B),        —SO_(v1.2)NR^(1.2B)R^(1.2C), —NHNR^(1.2B)R^(1.2C), —COOR^(1.2A),        —CONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A),        —CONR^(1.3B)R^(1.3C), —NO₂, —SR^(1.3D), —SO_(n1.3)R^(1.3B),        —SO_(v1.3)NR^(1.3B)R^(1.3C), —NHNR^(1.3B)R^(1.3)C,        —ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   X⁴ is N or CR¹³;    -   X⁵ is CR¹⁴R¹⁵, S, O, or NR^(20A);    -   R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,        —CI₃, —CN, —CHO, —OR^(8A), —NR^(8B)R^(8C), —COOR^(8A),        —CONR^(8B)R^(8C), —NO₂, —SR^(8D), —SO_(n8)R^(8B),        —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),        —NHC(O)NHNR^(8B)R^(8C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,        —CI₃, —CN, —CHO, —OR^(9A), —NR^(9B)R^(9C), —COOR^(9A),        —CONR^(9B)R^(9C), —NO₂, —SR^(9D), —SO_(n9)R^(9B),        —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),        —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(13A), —NR^(13B)R^(13C), —COOR^(13A),        —CONR^(13B)R^(13C), —NO₂, —SR^(13D), —SO_(n13)R^(13B),        —SO_(v13)NR^(13B)R^(13C), —NHNR^(13B)R^(13C), —ONR^(13B)R^(13C),        —NHC(O)NHNR^(13B)R^(13C), x substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(14A), —NR^(14B)R^(14C), —COOR^(14A),        —CONR^(14B)R^(14C), —NO₂, —SR^(14D), —SO_(n14)R^(14B),        —SO_(v14)NR^(14B)R^(14C), —NHNR^(14B)R^(14C), —ONR^(14B)R^(14C),        —NHC(O)NHNR^(14B)R^(14C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(15A), —NR^(15B)R^(15C), —COOR^(15A),        —CONR^(15B)R^(15C), —NO₂, —SR^(15D), —SO_(n15)R^(15B),        —SO_(v15)NR^(15B)R^(15C), —NHNR^(15B)R^(15C), —ONR^(15B)R^(15C),        —NHC(O)NHNR^(15B)R^(15C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A), R^(1.2B), R^(1.2C),        R^(1.2D), R^(1.3A), R^(1.3B), R^(1.3C), R^(1.3D), R^(8A),        R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(13A),        R^(13B), R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D),        R^(15A), R^(15B), R^(15C), R^(15D), and R^(20A) are        independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂,        —OCHI₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl; and R^(1.1B) and R^(1.1C), R^(1.2B)        and R^(1.2C), R^(1.3B) and R^(1.3C), R^(13B) and R^(13C),        R^(14B) and R^(14C), and R^(15B) and R^(15C), substituents        bonded to the same nitrogen atom may optionally be joined to        form a substituted or unsubstituted heterocycloalkyl or        substituted or unsubstituted heteroaryl;    -   n1.2, n1.3, n8, n9, n13, n14, and n15 are independently an        integer from 0 to 4; and    -   v1.2, v1.3, v8, v9, v13, v14, and v15 are independently 1 or 2.

Embodiment P14. The compound of embodiment P13, wherein the compound hasformula:

Embodiment P15. The compound of any one of embodiments P2 to P12,wherein R⁶ and R⁷ independently hydrogen.

Embodiment P16. The compound of any one of embodiments P2 to P6, whereinX² is N.

Embodiment P17. The compound of any one of embodiments P2 to P6, whereinR¹² is —OCH₃.

Embodiment P18. The compound of any one of embodiments P3 to P17,wherein R^(1.2) is substituted or unsubstituted alkyl.

Embodiment P19. The compound of any one of embodiments P3 to P18,wherein R^(1.2) is substituted or unsubstituted C₁-C₃alkyl.

Embodiment P20. The compound of any one of embodiments P3 to P19,wherein R^(1.2) is methyl.

Embodiment P21. The compound of any one of embodiments P3 to P20,wherein R^(1.3) is —CN.

Embodiment P22. The compound of any one of embodiments P1 to P21,wherein:

-   -   R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸; and    -   R⁵ is —C(O)-L²-R¹⁹ or —C(S)-L²-R¹⁹.

Embodiment P23. The compound of any one of embodiments P1 to P22,wherein:

-   -   R⁴ is —C(O)-L¹-R¹⁸; and    -   R⁵ is —C(O)-L²-R¹⁹.

Embodiment P24. The compound of any one of embodiments P1 to P22,wherein:

-   -   R⁴ is —C(S)-L¹-R¹⁸; and    -   R⁵ is —C(S)-L²-R¹⁹.

Embodiment P25. The compound of any one of embodiments P1 to P24,wherein L¹ and L² are independently —O—.

Embodiment P26. The compound of any one of embodiments P1 to P24,wherein L¹ and L² are independently —NH—.

Embodiment P27. The compound of any one of embodiments P1 to P24,wherein L¹ and L² are independently a bond.

Embodiment P28. The compound of any one of embodiments P1 to P24,wherein:

-   -   L¹ is -L^(1A)-L^(1B)-, wherein L^(1A) is bonded to —C(O)— or        —C(S)—; and    -   L² is -L^(2A)-L^(2B)-, wherein L^(2A) is bonded to —C(O)— or        —C(S)—;    -   L^(1A) is a bond or —(CH₂)_(z1)—;    -   L^(1B) is a bond, —O— or —NR^(16B)—;    -   L^(2A) is a bond or —(CH₂)_(z2)—;    -   L^(2B) is a bond, —O— or —NR^(17B)—;    -   z1 and z2 are independently an integer from 1 to 10; and    -   R^(16B) and R^(17B) are independently hydrogen or substituted or        unsubstituted alkyl.

Embodiment P29. The compound of embodiment P28, wherein L^(1A) andL^(2A) are independently —CH₂—.

Embodiment P30. The compound of embodiments P28 or P29, wherein:

-   -   L^(1B) is —NR^(16B);    -   L^(2B) is —NR^(17B); and    -   R^(16B) and R^(17B) are independently unsubstituted C₁-C₃alkyl.

Embodiment P31. The compound of any one of embodiments P1 to P30,wherein R¹⁸ and R¹⁹ are independently unsubstituted C₁-C₃alkyl orunsubstituted aryl.

Embodiment P32. The compound of any one of embodiments P1 to P31,wherein R¹⁸ and R¹⁹ are independently unsubstituted aryl.

Embodiment P33. The compound of any one of embodiments P1 to P30,wherein R¹⁸ and R¹⁹ are independently halogen.

Embodiment P34. The compound of any one of embodiments P1 to P21,wherein R⁴ and R⁵ are joined together to form:

Embodiment P35. The compound of any one of embodiments P1 to P34,wherein R² is methyl.

Embodiment P36. The compound of embodiment P1, wherein the compound hasthe structure:

Embodiment P37. A method of treating cancer, comprising administering toa subject in need thereof a therapeutically effective amount of acompound of any one of embodiments P1 to P36.

Embodiment P38. The method of embodiment P37, wherein the cancer is asolid or blood tumor.

Embodiment P39. The method of embodiment P37, wherein the cancer isovarian cancer, breast cancer, lung cancer, leukemia, AML, CML,lymphoma, pancreatic cancer, kidney cancer, melanoma, liver cancer,colon cancer, sarcoma, multiple myeloma, brain cancer, or prostatecancer.

Embodiment P40. The method of any one of embodiments P37 to P39, furthercomprising administering at least one additional anticancer agent.

Embodiment 41. The method of embodiment 40, wherein the at least oneadditional anticancer agent comprises an epigenetic inhibitor or amulti-kinase inhibitor.

Embodiment 42. The method of any one of embodiments P37 to P41, whereinthe method comprises administering a first amount of the compound and asecond amount of at least one additional anticancer agent, wherein thefirst amount and second amount are together an effective amount toprovide a synergistic therapeutic effect.

Embodiment P43. The method of any one of embodiments P40 to P42, whereinthe additional anticancer agent is an epigenetic inhibitor.

Embodiment P44. The method of embodiment P43, wherein the epigeneticinhibitor is azacitidine or decitadine.

Embodiment P45. The method of embodiments P43 or P44, wherein thecompound and the epigenetic inhibitor are co-administered as apharmaceutical composition.

Embodiment P46. The method of any one of embodiments P40 to P42, whereinthe additional anticancer agent is a multi-kinase inhibitor.

Embodiment P47. The method of embodiment P46, wherein the multi-kinaseinhibitor is sorafenib.

Embodiment P48. The method of embodiments P46 or P47, wherein thecompound and the multi-kinase inhibitor are co-administered as apharmaceutical composition.

Embodiment P49. The method of embodiment P37 or P39, wherein the canceris ovarian cancer.

Embodiment P50. A pharmaceutical composition comprising a compound ofany one of embodiments P1 to P36 and a pharmaceutically acceptableexcipient.

Embodiment P51. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a combination of a compound ofany one of embodiments P1 to P36 and at least one additional anticanceragent.

Embodiment P52. The pharmaceutical composition of embodiment P51,wherein the at least one additional anticancer agent comprises amulti-kinase inhibitor or an epigenetic inhibitor.

Embodiment P53. The pharmaceutical composition of embodiment P51,wherein the combination includes a first amount of the compound and asecond amount of a multi-kinase inhibitor, wherein the first amount andsecond amount are together an effective amount to provide a synergistictherapeutic effect.

Embodiment P54. The pharmaceutical composition of embodiment P51,wherein the combination includes a first amount of the compound and asecond amount of an epigenetic inhibitor, wherein the first amount andsecond amount are together an effective amount to provide a synergistictherapeutic effect.

Embodiment P55. The pharmaceutical composition of embodiment P51,wherein the combination includes a first amount of the compound, asecond amount of a multi-kinase inhibitor, and a third amount of anepigenetic inhibitor, wherein the first amount, second, and thirdamounts are together an effective amount to provide a synergistictherapeutic effect.

Embodiment P56. The pharmaceutical composition of embodiments P52 orP55, wherein the multi-kinase inhibitor is sorafenib and the epigeneticinhibitor is azacitidine or decitabine.

Embodiment P57. The pharmaceutical composition of any one of embodimentP50 to P56 for use in cancer.

Embodiment P58. The pharmaceutical composition of any one of embodimentsP50 to P56 for use in solid and blood tumors, including ovarian cancer,breast cancer, lung cancer, leukemia, AML, CML, lymphoma, pancreaticcancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma,multiple myeloma, brain cancer, or prostate cancer.

Embodiment P59. The pharmaceutical composition of any one of embodimentsP50 to P56 for use in non-small cell lung cancer.

Embodiment P60. The pharmaceutical composition of any one of embodimentsP52, P55 or P56, wherein the compound and the multi-kinase inhibitor orthe epigenetic inhibitor are co-administered as a single dosage form.

Embodiment P61. A method of inhibiting the growth of a cancer cell,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of any one of embodiments P1 to P36.

Embodiment P62. The method of embodiment P61, wherein the cancer cell isan ovarian cancer cell, breast cancer cell, lung cancer cell, leukemiacell, AML cell, CML cell, lymphoma cell, pancreatic cancer cell, kidneycancer cell, melanoma cell, liver cancer cell, colon cancer cell,sarcoma cell, multiple myeloma cell, brain cancer cell, or prostatecancer cell.

EMBODIMENTS

Embodiment 1. A compound having the formula:

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(1A), —NR^(1B)R^(1C), —C(O)OR^(1A),        —C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D), —S(O)_(n1)NR^(1B),        —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),        —NHC(O)NHNR^(1B)R^(1C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —COOR^(2A),        —CONR^(2B)R^(2C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C),        —NO₂, —SR^(3D), —SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C),        —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸;    -   R⁵ is —C(O)-L²-R¹⁹ or —C(S)-L²-R¹⁹; or    -   R⁴ and R⁵ may optionally be joined to form

-   -   L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   R¹⁸ and R¹⁹ are independently halogen, substituted or        unsubstituted C₁-C₃alkyl, substituted or unsubstituted aryl;    -   R²⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(25A), —NR^(25B)R^(25C), —C(O)OR^(25A),        —C(O)NR^(25B)R^(25C), —NO₂, —SR^(25D), —S(O)_(n25)R^(25B),        —SO_(v25)NR^(25B)R^(25C), —NHNR^(25B)R^(25C), ONR^(25B)R^(25C),        —NHC(O)NHNR^(25B)R^(25C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(3A),        R^(3B), R^(3C), R^(3D), R^(25A), R^(25B), R^(25C), and R^(25D)        are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,        —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,        —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,        —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,        —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; and R^(1B) and R^(1C),        R^(2B) and R^(2C), R^(3B) and R^(3C), and R^(25B) and R^(25C)        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl;    -   z3 is an integer from 0 to 5;    -   n1, n3, and n25 are independently an integer from 0 to 4; and    -   v1, v3, and v25 are independently 1 or 2.

Embodiment 2. The compound of embodiment 1, wherein the compound has theformula:

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   X¹ is N or CR¹⁰;    -   X² is N or CR¹¹;    -   X³ is N or CR¹²;    -   R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C),        —NO₂, —SR^(6D), —SO_(n6)R^(6B), —SO_(v6)NR^(6B)R^(6C),        —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C),        —NO₂, —SR^(7D), —SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C),        —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(10A), —NR^(10B)R^(10C), —COOR^(10A),        —CONR^(10B)R^(10C), —NO₂, —SR^(10D), —SO_(n10)R^(10B),        —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),        —NHC(O)NHNR^(10B)R^(10C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(11A), —NR^(11B)R^(11C), —COOR^(11A),        —CONR^(11B)R^(11C), —NO₂, —SR^(11D), —SO_(n11)R^(11B),        —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C), —ONR^(11B)R^(11C),        —NHC(O)NHNR^(11B)R^(11C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R¹⁰ and R¹¹ may        optionally be joined to form a substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl;    -   R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(12A), —NR^(12B)R^(12C), —COOR^(12A),        —CONR^(12B)R^(12C), —NO₂, —SR^(12D), —SO_(n12)R^(12B),        —SO_(v12)NR^(12B)R^(12C), —NHNR^(12B)R^(12C), —ONR^(12B)R^(12C),        —NHC(O)NHNR^(12B)R^(12C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R¹¹ and R¹² may        optionally be joined to form a substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl;    -   R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D),        R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C),        R^(11D), R^(12A), R^(12B), R^(12C), and R^(12D) are        independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂,        —OCHI₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl; and R^(6B) and R^(6C), R^(7B) and        R^(7C), R^(10B) and R^(10C), R^(11B) and R^(11C), and R^(12B)        and R^(12C), substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl;    -   n6, n7, n10, n11 and n12 are independently an integer from 0 to        4; and    -   v6, v7, v10, v11 and v12, are independently 1 or 2.

Embodiment 3. The compound of embodiment 2, wherein the compound hasstructural formula:

wherein:

-   -   R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A),        —CONR^(1.2B)R^(1.2C), —NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B),        —SO_(v1.2)NR^(1.2B)R^(1.2C), —NHNR^(1.2B)R^(1.2C),        —ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A),        —CONR^(1.3B)R^(1.3C), —NO₂, —SR^(1.3D), —SO_(n1.3)R^(1.3B),        —SO_(v1.3)NR^(1.3B)R^(1.3C), —NHNR^(1.3B)R^(1.3C),        —ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.4) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.4A), —NR^(1.4B)R^(1.4C), —COOR^(1.4A),        —CONR^(1.4B)R^(1.4C), —NO₂, —SR^(1.4D), —SO_(n1.4)R^(1.4B),        —SO_(v1.4)NR^(1.4B)R^(1.4C), —NHNR^(1.4B)R^(1.4C),        —ONR^(1.4B)R^(1.4C), —NHC(O)NHNR^(1.4B)R^(1.4C), substituted or        unsubstituted alkyl, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1.5) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,        —CN, —CHO, —OR^(1.5A), —NR^(1.5B)R^(1.5C), —COOR^(1.5A),        —CONR^(1.5B)R^(1.5C), —NO₂, —SR^(1.5D), —SO_(n1.5)R^(1.5B),        —SO_(v1.5)NR^(1.5B)R^(1.5C), —NHNR^(1.5B)R^(1.5C),        —ONR^(1.5B)R^(1.5C), —NHC(O)NHNR^(1.5B)R^(1.5C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A), and R^(1.2B), R^(1.2C),        R^(1.2D), R^(1.3A), R^(1.3B), and R^(1.3C), R^(1.3D), R^(1.4A),        R^(1.4B), R^(1.4C), and R^(1.5D), R^(1.5A), R^(1.5B), R^(1.5C),        and R^(1.5D) are independently hydrogen, halogen, —CF₃, —CCl₃,        —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,        —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,        —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,        —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; and R^(1.1B) and        R^(1.1C), R^(1.2B) and R^(1.2C), R^(1.3B) and R^(1.3C), R^(1.4B)        and R^(1.4C), and R^(1.5B) and R^(1.5C) substituents bonded to        the same nitrogen atom may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl or substituted or        unsubstituted heteroaryl;    -   n1.2, n1.3, n1.4, and n1.5 are independently an integer from 0        to 4; and    -   v1.2, v1.3, v1.4, and v1.5 are independently 1 or 2.

Embodiment 4. The compound of embodiment 3, wherein the compound hasstructural formula:

Embodiment 5. The compound of any one of embodiments 2 to 4, wherein R¹⁰and R¹¹ or R¹¹ and R¹² are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

-   -   wherein:    -   X⁶ is O, NR^(23A), or S;    -   X⁷ is O, NR^(24A), or S;    -   z4 is an integer from 0 to 2;    -   z5 is an integer from 0 to 8;    -   m is 1 or 2;    -   R²¹, R²², R^(23A), and R^(24A) are independently hydrogen,        halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,        —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂,        —OCHF₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl.

Embodiment 6. The compound of embodiments 3 or 4, wherein the compoundhas the formula:

Embodiment 7. The compound of embodiment 5, wherein the compound has theformula:

Embodiment 8. The compound of embodiment 7, wherein the compound has theformula:

Embodiment 9. The compound of embodiment 5, wherein the compound has theformula:

Embodiment 10. The compound of embodiment 9, wherein the compound hasformula:

Embodiment 11. The compound of embodiment 5, wherein the compound hasthe formula:

Embodiment 12. The compound of embodiment 11, wherein the compound hasformula:

Embodiment 13. The compound of embodiment 1, wherein the compound hasstructural formula:

-   -   wherein:    -   R^(1.1) is hydrogen, halogen, —CF₃, —CCl₃, CI₃, —CN, —CHO,        —COOR^(1.1A), —CONR^(1.1B)R^(1.1C), substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1.2) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, CI₃, —CN, —CHO,        —OR^(1.2A), —NR^(1.2B)R^(1.2C), —COOR^(1.2A),        —CONR^(1.2B)R^(1.2C), —NO₂, —SR^(1.2D), —SO_(n1.2)R^(1.2B),        —SO_(v1.2)NR^(1.2B)R^(1.2C), —NHNR^(1.2B)R^(1.2C),        —ONR^(1.2B)R^(1.2C), —NHC(O)NHNR^(1.2B)R^(1.2C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1.3) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, CI₃, —CN, —CHO,        —OR^(1.3A), —NR^(1.3B)R^(1.3C), —COOR^(1.3A),        —CONR^(1.3B)R^(1.3C), —NO₂, —SR^(1.3D), —SO_(n1.3)R^(1.3B),        —SO_(v1.3)NR^(1.3B)R^(1.3C), —NHNR^(1.3B)R^(1.3C),        —ONR^(1.3B)R^(1.3C), —NHC(O)NHNR^(1.3B)R^(1.3C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   X⁴ is N or CR¹³;    -   X⁵ is CR¹⁴R¹⁵, S, O, or NR^(20A);    -   R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(8A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C),        —NO₂, —SR^(8D), —SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C),        —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C),        —NO₂, —SR^(9D), —SO_(n9)R^(9B), —SO_(v9)NR^(9B)R^(9C),        —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(13A), —NR^(13B)R^(13C), —COOR^(13A),        —CONR^(13B)R^(13C), —NO₂, —SR^(13D), —SO_(n13)R^(13B),        —SO_(v13)NR^(13B)R^(13C), —NHNR^(13B)R^(13C), —ONR^(13B)R^(13C),        —NHC(O)NHNR^(13B)R^(13C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(14A), —NR^(14B)R^(14C), —COOR^(14A),        —CONR^(14B)R^(14C), —NO₂, —SR^(14D), —SO_(n14)R^(14B),        —SO_(v14)NR^(14B)R^(14C), —NHNR^(14B)R^(14C), —ONR^(14B)R^(14C),        —NHC(O)NHNR^(14B)R^(14C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(15A), —NR^(15B)R^(15C), —COOR^(15A),        —CONR^(15B)R^(15C), —SR^(15D), —SO_(n15)R^(15B),        —SO_(v15)NR^(15B)R^(15C), —NHNR^(15B)R^(15C), —ONR^(15B)R^(15C),        —NHC(O)NHNR^(15B)R^(15C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1.1A), R^(1.1B), R^(1.1C), R^(1.2A), R^(1.2B), R^(1.2C),        R^(1.2D), R^(1.3A), R^(1.3B), R^(1.3C), R^(1.3D), R^(8A),        R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(13A),        R^(13B), R^(13C), R^(13D), R^(14A), R^(14B), R^(14C), R^(14D),        R^(15A), R^(15B), R^(15C), R^(15D), and R^(20A) are        independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂,        —OCHI₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl; and R^(1.1B) and R^(1.1C), R^(1.2B)        and R^(1.2C), R^(1.3B) and R^(1.3C), R^(13B) and R^(13C),        R^(14B) and R^(14C), and R^(15B) and R^(15C), substituents        bonded to the same nitrogen atom may optionally be joined to        form a substituted or unsubstituted heterocycloalkyl or        substituted or unsubstituted heteroaryl;    -   n1.2, n1.3, n8, n9, n13, n14, and n15 are independently an        integer from 0 to 4; and    -   v1.2, v1.3, v8, v9, v13, v14, and v15 are independently 1 or 2.

Embodiment 14. The compound of embodiment 13, wherein the compound hasformula:

Embodiment 15. The compound of any one of embodiments 2 to 12, whereinR⁶ and R⁷ independently hydrogen.

Embodiment 16. The compound of any one of embodiments 2 to 6, wherein X²is N.

Embodiment 17. The compound of any one of embodiments 2 to 6, whereinR¹² is —OCH₃.

Embodiment 18. The compound of any one of embodiments 3 to 17, whereinR¹² is substituted or unsubstituted alkyl.

Embodiment 19. The compound of any one of embodiments 3 to 18, whereinR¹² is substituted or unsubstituted C₁-C₃alkyl.

Embodiment 20. The compound of any one of embodiments 3 to 19, whereinR^(1.2) is methyl.

Embodiment 21. The compound of any one of embodiments 3 to 20, whereinR^(1.3) is —CN.

Embodiment 22. The compound of any one of embodiments 1 to 21, wherein:

-   -   R⁴ is —C(O)-L¹-R¹⁸ or —C(S)-L¹-R¹⁸; and    -   R⁵ is —C(O)-L²-R¹⁹ or —C(S)-L²-R¹⁹.

Embodiment 23. The compound of any one of embodiments 1 to 22, wherein:

-   -   R⁴ is —C(O)-L¹-R¹⁸; and    -   R⁵ is —C(O)-L²-R¹⁹.

Embodiment 24. The compound of any one of embodiments 1 to 22, wherein:

-   -   R⁴ is —C(S)-L¹-R¹⁸; and    -   R⁵ is —C(S)-L²-R¹⁹.

Embodiment 25. The compound of any one of embodiments 1 to 24, whereinL¹ and L² are independently —O—.

Embodiment 26. The compound of any one of embodiments 1 to 24, whereinL¹ and L² are independently —NH—.

Embodiment 27. The compound of any one of embodiments 1 to 24, whereinL¹ and L² are independently a bond.

Embodiment 28. The compound of any one of embodiments 1 to 24, wherein:

-   -   L¹ is -L^(1A)-L^(1B)-, wherein L^(1A) is bonded to —C(O)— or        —C(S)—; and    -   L² is -L^(2A)-L^(2B), wherein L^(2A) is bonded to —C(O)— or        —C(S)—;    -   L^(1A) is a bond or —(CH₂)_(z1)—;    -   L^(1B) is a bond, —O— or —NR^(16B)—;    -   L^(2A) is a bond or —(CH₂)_(z2)—;    -   L^(2B) is a bond, —O— or —NR^(17B)—;    -   z1 and z2 are independently an integer from 1 to 10; and    -   R^(16B) and R^(17B) are independently hydrogen or substituted or        unsubstituted alkyl.

Embodiment 29. The compound of embodiment 28, wherein L^(1A) and L^(2A)are independently —CH₂—.

Embodiment 30. The compound of embodiments 28 or 29, wherein:

-   -   L^(1B) is —NR^(16B);    -   L^(2B) is —NR^(17B); and    -   R^(16B) and R^(17B) are independently unsubstituted C₁-C₃alkyl.

Embodiment 31. The compound of any one of embodiments 1 to 30, whereinR¹⁸ and R¹⁹ are independently unsubstituted C₁-C₃alkyl or unsubstitutedaryl.

Embodiment 32. The compound of any one of embodiments 1 to 31, whereinR¹⁸ and R¹⁹ are independently unsubstituted aryl.

Embodiment 33. The compound of any one of embodiments 1 to 30, whereinR¹⁸ and R¹⁹ are independently halogen.

Embodiment 34. The compound of any one of embodiments 1 to 21, whereinR⁴ and R⁵ are joined together to form:

Embodiment 35. The compound of any one of embodiments 1 to 34, whereinR² is methyl.

Embodiment 36. The compound of embodiment 1, wherein the compound hasthe structure:

Embodiment 37. A method of treating cancer, comprising administering toa subject in need thereof a therapeutically effective amount of acompound of any one of embodiments 1 to 36.

Embodiment 38. The method of embodiment 37, wherein the cancer is asolid or blood tumor.

Embodiment 39. The method of embodiment 37, wherein the cancer isovarian cancer, breast cancer, lung cancer, leukemia, AML, CML,lymphoma, pancreatic cancer, kidney cancer, melanoma, liver cancer,colon cancer, sarcoma, multiple myeloma, brain cancer, or prostatecancer.

Embodiment 40. The method of any one of embodiments 37 to 39, furthercomprising administering at least one additional anticancer agent.

Embodiment 41. The method of embodiment 40, wherein the at least oneadditional anticancer agent comprises an epigenetic inhibitor or amulti-kinase inhibitor.

Embodiment 42. The method of any one of embodiment 37 to 41, wherein themethod comprises administering a first amount of the compound and asecond amount of at least one additional anticancer agent, wherein thefirst amount and second amount are together an effective amount toprovide a synergistic therapeutic effect.

Embodiment 43. The method of any one of embodiments 40 to 42, whereinthe additional anticancer agent is an epigenetic inhibitor.

Embodiment 44. The method of embodiment 43, wherein the epigeneticinhibitor is azacitidine or decitadine.

Embodiment 45. The method of embodiments 43 or 44, wherein the compoundand the epigenetic inhibitor are co-administered as a pharmaceuticalcomposition.

Embodiment 46. The method of any one of embodiments 40 to 42, whereinthe additional anticancer agent is a multi-kinase inhibitor.

Embodiment 47. The method of embodiment 46, wherein the multi-kinaseinhibitor is sorafenib.

Embodiment 48. The method of embodiments 46 or 47, wherein the compoundand the multi-kinase inhibitor are co-administered as a pharmaceuticalcomposition.

Embodiment 49. The method of embodiment 37 or 39, wherein the cancer isovarian cancer.

Embodiment 50. A pharmaceutical composition comprising a compound of anyone of embodiments 1 to 36 and a pharmaceutically acceptable excipient.

Embodiment 51. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a combination of a compound ofany one of embodiments 1 to 36 and at least one additional anticanceragent.

Embodiment 52. The pharmaceutical composition of embodiment 51, whereinthe at least one additional anticancer agent comprises a multi-kinaseinhibitor or an epigenetic inhibitor.

Embodiment 53. The pharmaceutical composition of embodiment 51, whereinthe combination includes a first amount of the compound and a secondamount of a multi-kinase inhibitor, wherein the first amount and secondamount are together an effective amount to provide a synergistictherapeutic effect.

Embodiment 54. The pharmaceutical composition of embodiment 51, whereinthe combination includes a first amount of the compound and a secondamount of an epigenetic inhibitor, wherein the first amount and secondamount are together an effective amount to provide a synergistictherapeutic effect.

Embodiment 55. The pharmaceutical composition of embodiment 51, whereinthe combination includes a first amount of the compound, a second amountof a multi-kinase inhibitor, and a third amount of an epigeneticinhibitor, wherein the first amount, second, and third amounts aretogether an effective amount to provide a synergistic therapeuticeffect.

Embodiment 56. The pharmaceutical composition of embodiment 52 or 55,wherein the multi-kinase inhibitor is sorafenib and the epigeneticinhibitor is azacitidine or decitabine.

Embodiment 57. The pharmaceutical composition of any one of embodiments50 to 56 for use in cancer.

Embodiment 58. The pharmaceutical composition of any one of embodiments50 to 56 for use in solid and blood tumors, including ovarian cancer,breast cancer, lung cancer, leukemia, AML, CML, lymphoma, pancreaticcancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma,multiple myeloma, brain cancer, or prostate cancer.

Embodiment 59. The pharmaceutical composition of any one of embodiments50 to 56 for use in non-small cell lung cancer.

Embodiment 60. The pharmaceutical composition of any one of embodiments52, 55 or 56, wherein the compound and the multi-kinase inhibitor or theepigenetic inhibitor are co-administered as a single dosage form.

Embodiment 61. A method of inhibiting the growth of a cancer cell,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of any one of embodiments 1 to 36.

Embodiment 62. The method of embodiment 61, wherein the cancer cell isan ovarian cancer cell, breast cancer cell, lung cancer cell, leukemiacell, AML cell, CML cell, lymphoma cell, pancreatic cancer cell, kidneycancer cell, melanoma cell, liver cancer cell, colon cancer cell,sarcoma cell, multiple myeloma cell, brain cancer cell, or prostatecancer cell.

1.-36. (canceled)
 37. A method of treating cancer, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: X is C or N; R¹is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —COOR^(1A),—CONR^(1B)R^(1C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, CI₃, —CN, —CHO, —OR^(2A),—NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C), —NO₂, —SR^(2D),—SO_(n2)R^(2B), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C), —C(O)OR^(3A), —C(O)NR^(3B)R^(3C), —NO₂,—SR^(3D), —S(O)_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C) substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R is hydrogen, halogen, —N₃, —CF₃, —CCl₃, CI₃, —CN, —CHO,—OR^(A), —NR^(B)R^(C), —C(O)OR^(A), —C(O)NR^(B)R^(C), —NO₂, —SR^(D),—S(O)_(n)R^(B), —SO_(v)NR^(B)R^(C), —NHNR^(B)R^(C), ONR^(B)R^(C),—NHC(O)NHNR^(B)R^(C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1A),R^(1B), R^(1C), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C),R^(3D), R^(A), R^(B), R^(C), and R^(D) are independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C), and R^(B) andR^(C) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; n2, n3, and n are independentlyan integer from 0 to 4; and v2, v3, and v are independently 1 or
 2. 38.The method of claim 37, wherein the cancer is a solid or blood tumor.39. The method of claim 37, wherein the cancer is ovarian cancer, breastcancer, lung cancer, leukemia, AML, CML, lymphoma, pancreatic cancer,kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, multiplemyeloma, brain cancer, or prostate cancer.
 40. The method of claim 37,further comprising administering at least one additional anticanceragent.
 41. The method of claim 40, wherein the at least one additionalanticancer agent comprises an epigenetic inhibitor or a multi-kinaseinhibitor.
 42. The method of claim 37, wherein the method comprisesadministering a first amount of the compound and a second amount of atleast one additional anticancer agent, wherein the first amount andsecond amount are together an effective amount to provide a synergistictherapeutic effect.
 43. The method of claim 40, wherein the additionalanticancer agent is an epigenetic inhibitor.
 44. The method of claim 43,wherein the epigenetic inhibitor is azacitidine or decitadine.
 45. Themethod claim 43, wherein the compound and the epigenetic inhibitor areco-administered as a pharmaceutical composition.
 46. The method of claim40, wherein the additional anticancer agent is a multi-kinase inhibitor.47. The method of claim 46, wherein the multi-kinase inhibitor issorafenib.
 48. The method of claim 46, wherein the compound and themulti-kinase inhibitor are co-administered as a pharmaceuticalcomposition.
 49. The method of claim 37, wherein the cancer is ovariancancer. 50.-60. (canceled)
 61. A method of inhibiting the growth of acancer cell, comprising administering to a subject in need thereof atherapeutically effective amount of a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: X is C or N; R¹is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —COOR^(1A),—CONR^(1B)R^(1C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(2A),—NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C), —NO₂, —SR^(2D),—SO_(n2)R^(2B), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(3A), —NR^(3B)R^(3C), —C(O)OR^(3A), —C(O)NR^(3B)R^(3C), —NO₂,—SR^(3D), —S(O)_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(A), —NR^(B)R^(C), —C(O)OR^(A), —C(O)NR^(B)R^(C), —NO₂,—SR^(D), —S(O)_(n)R^(B), —SO_(v)NR^(B)R^(C), —NHNR^(B)R^(C),ONR^(B)R^(C), —NHC(O)NHNR^(B)R^(C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1A), R^(1B), R^(1C), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B),R^(3C), R^(A), R^(B), R^(C), and R^(D) are independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C), and R^(B) andR^(C) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; n2, n3, and n are independentlyan integer from 0 to 4; and v2, v3, and v are independently 1 or
 2. 62.The method of claim 61, wherein the cancer cell is an ovarian cancercell, breast cancer cell, lung cancer cell, leukemia cell, AML cell, CMLcell, lymphoma cell, pancreatic cancer cell, kidney cancer cell,melanoma cell, liver cancer cell, colon cancer cell, sarcoma cell,multiple myeloma cell, brain cancer cell, or prostate cancer cell. 63.The method of claim 37, wherein the compound is of the formula:


64. The method of claim 37, wherein the compound is of the formula:


65. The method of claim 61, wherein the compound is of the formula:


66. The method of claim 61, wherein the compound is of the formula: